Details of the Researcher

PHOTO

Yasutoshi Akiyama
Section
Graduate School of Pharmaceutical Sciences
Job title
Assistant Professor
Degree

  • 博士（医学）（東北大学）

Research Interests 5

  • 高血圧

  • ミトコンドリア病

  • 腎臓病学

  • tRNAs

  • RNAの分子生物学

Papers 44

  1. RNase L Produces tRNA-derived RNAs that Contribute to Translation Inhibition. International-journal Peer-reviewed

    Yoshika Takenaka, Asuka Yamada, Yoshihisa Tomioka, Yasutoshi Akiyama, Pavel Ivanov

    RNA (New York, N.Y.)　2025/04/15

    DOI： 10.1261/rna.080419.125 　

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    Ribonuclease L (RNase L) is an RNase which is activated by viral double-stranded RNAs (dsRNAs). RNase L cleaves not only viral RNAs but also host RNAs including mRNAs and tRNAs, which contributes to innate immune defense against viruses. While it has been reported that RNase L-mediated bulk mRNA cleavage induces rapid translation repression independently of the integrated stress response, the significance of RNase L-mediated tRNA cleavage remains largely unknown. Here we show that RNase L cleaves various tRNA species in the anticodon loops, generating transfer RNA-derived RNAs (tDRs) similar to tRNA-derived stress-induced RNAs (tiRNAs) that are generated by a stress-responsive RNase angiogenin (ANG). Three tRNA species (tRNALeu, tRNASeC and tRNASer) were cleaved within the variable loops as well as in the anticodon loops by RNase L, generating non-canonical tDRs. As RNase L-induced 5'-tDRAla/Cys were similar in length to 5'-tiRNAAla/Cys that possess a translation inhibitory effect, we examined whether RNase L-induced 5'-tDRAla also inhibited translation. In vitro translation analysis showed that RNase L-induced 5'-tDRAla significantly inhibits mRNA translation like 5'-tiRNAAla, suggesting that the production of 5'-tDRAla may be involved in the mechanism of RNase L-mediated stress response during viral infection. Our data shed new light on the potential roles of tDRs in innate immunity against viral infection.

  2. Hypoglycemia and hyperinsulinemia induced by phenolic uremic toxins in CKD and DKD patients. International-journal Peer-reviewed

    Yoshiyasu Tongu, Tomoko Kasahara, Yasutoshi Akiyama, Takehiro Suzuki, Hsin-Jung Ho, Yotaro Matsumoto, Ryota Kujirai, Koichi Kikuchi, Koji Nata, Makoto Kanzaki, Kenshin Suzuki, Shun Watanabe, Chiharu Kawabe, Yui Miyata, Shun Itai, Takafumi Toyohara, Chitose Suzuki, Tetsuhiro Tanaka, Jun Wada, Yoshihisa Tomioka, Takaaki Abe

    Scientific reports　15　(1)　5762-5762　2025/02/17

    DOI： 10.1038/s41598-025-87501-x 　

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    Patients with end-stage renal disease have lower fasting plasma glucose and HbA1c levels, with significantly higher insulin levels. For a long time, it has been believed that this higher insulin level in renal failure is due to decreased insulin clearance caused by reduced renal function. However, here we reported that accumulation of the gut microbiota-derived uremic toxin, phenyl sulfate (PS) in the renal failure, increased insulin secretion from the pancreas by enhanced glucose-stimulated insulin secretion. Other endogenous sulfides compounds which accumulated as in the renal failure also increased glucose-stimulated insulin secretion from β-cell. With RNA-seq analyses and gene knock down, we demonstrated that insulin secretion evoked by PS was mediated by Ddah2. In addition, we also found that PS increased insulin resistance through lncRNA expression and Erk phosphorylation in the adipocytes. To confirm the relationship between PS and glucose metabolism in human, we recruited 2 clinical cohort studies (DKD and CKD) including 462 patients, and found that there was a weak negative correlation between PS and HbA1c. Because these trials did not measure fasting insulin level, we alternatively used the urinary C-peptide/creatinine ratio (UCPCR) as an indicator of insulin resistance. We found that PS may induce insulin resistance in patients with eGFR < 60 mL/min/1.73 m2. These data suggest that the accumulation of uremic toxins modulates glucose metabolism and induced insulin resistance in CKD and DKD patients. Considering HbA1c as a reflection of chronic hyperglycemia and UCPCR as a reflection of chronic hyperinsulinemia, our findings indicate that PS is negatively associated with hyperglycemia independent of CKD, and positively associated with hyperinsulinemia in DKD patients.

  3. Purification of endogenous tDRs by hybridization-based pulldown. International-journal Invited Peer-reviewed

    Yoshika Takenaka, Nana Kunii, Yasutoshi Akiyama

    Methods in enzymology　711　1-14　2025

    DOI： 10.1016/bs.mie.2024.11.019 　

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    As transfer RNAs (tRNAs) are characterized by the existence of a variety of post-transcriptional modifications, transfer RNA-derived RNAs (tDRs) also possess various modifications. Accumulating evidence suggests that these modifications can regulate the biogenesis and the biological functions of tDRs. Therefore, it is important to purify endogenous tDRs for examining the physiological roles of tDRs. Here we present a simple protocol for purification of endogenous tDRs by hybridization-based pulldown. In this method, tDRs of interest are hybridized to biotinylated oligo DNA probes, followed by pulldown using a streptavidin agarose resin. Resin-bound tDR-probe complexes are then isolated by competitive dissociation using excess amount of biotin. After digestion of probes by DNase I, the purified tDRs are obtained. As the pulldown efficiency of this method largely depends on how efficiently tDRs are generated, the yield can be significantly improved by combination with methods for efficient tDR production, such as in lysate RNA digestion method that we previously reported.

  4. Northern blotting for human pre-tRNA and tRNA-derived RNAs. International-journal Invited Peer-reviewed

    Yoshika Takenaka, Katsuki Aoyama, Yasutoshi Akiyama

    Methods in enzymology　711　15-27　2025

    DOI： 10.1016/bs.mie.2024.11.013 　

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    Northern blotting (NB) is a classic method for visualizing the length as well as the amount of specific RNA using gel separation and hybridization probes. As transfer RNA-derived RNAs (tDRs) are generated from mature tRNAs or pre-tRNAs, the ratio of tDR to mature tRNA or pre-tRNA will be a useful information about the efficiency of tDR production. By designing NB probes which hybridize to a mature tRNA of interest, the blot can simultaneously visualize the amount of tDRs as well as mature tRNAs and pre-tRNAs originated from the same gene, which is a significant advantage of NB. In this chapter, we present a protocol for the detection of tDRs or pre-tRNAs by NB using denaturing polyacrylamide gel electrophoresis and Digoxigenin-dUTP-tailed oligo DNA probes. Through example experiments, we show that tDRs originating from the same mature tRNA can be differentiated based on their length. We also show that our method can be applied to the evaluation of pre-tRNA processing.

  5. Chronopharmacology of diuresis via metabolic profiling and key biomarker discovery of the Traditional Chinese Prescription Ji-Ming-San using tandem mass spectrometry in rat models Peer-reviewed

    Cheng-Yang Hsieh, Po-Wei Tsai, Yoshihisa Tomioka, Yotaro Matsumoto, Yasutoshi Akiyama, Ching-Chiung Wang, Lemmuel L. Tayo, Chia-Jung Lee

    Phytomedicine　155260-155260　2023/12

    Publisher: Elsevier BV

    DOI： 10.1016/j.phymed.2023.155260 　

    ISSN： 0944-7113

  6. tRNA‐derived RNAs: Biogenesis and roles in translational control Peer-reviewed

    Yasutoshi Akiyama, Pavel Ivanov

    WIREs RNA　2023/11

    DOI： 10.1002/wrna.1805 　

  7. Oxidative stress, tRNA metabolism and protein synthesis Peer-reviewed

    Yasutoshi Akiyama, Pavel Ivanov

    Antioxidants & Redox Signaling　2023/09/28

    Publisher: Mary Ann Liebert Inc

    DOI： 10.1089/ars.2022.0206 　

    ISSN： 1523-0864

    eISSN： 1557-7716

  8. CD98 regulates the phosphorylation of HER2 and a bispecific anti‐HER2/CD98 antibody inhibits the growth signal of human breast cancer cells Peer-reviewed

    Akitaka Yamasaki, Kumiko Maruyama‐Takahashi, Kento Nishida, Shogo Okazaki, Kouki Okita, Yasutoshi Akiyama, Hideaki Suzuki, Yuichi Endo, Kazue Masuko, Takashi Masuko, Yoshihisa Tomioka

    Genes to Cells　2023/02/21

    Publisher: Wiley

    DOI： 10.1111/gtc.13016 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  9. Dual‐targeting therapy against HER3/MET in human colorectal cancers Peer-reviewed

    Akitaka Yamasaki, Rikuto Miyake, Yuta Hara, Hideki Okuno, Takuya Imaida, Kouki Okita, Shogo Okazaki, Yasutoshi Akiyama, Kenji Hirotani, Yuichi Endo, Kazue Masuko, Takashi Masuko, Yoshihisa Tomioka

    Cancer Medicine　2023/02/07

    Publisher: Wiley

    DOI： 10.1002/cam4.5673 　

    ISSN： 2045-7634

    eISSN： 2045-7634

  10. RTCB Complex Regulates Stress-Induced tRNA Cleavage Peer-reviewed

    Yasutoshi Akiyama, Yoshika Takenaka, Tomoko Kasahara, Takaaki Abe, Yoshihisa Tomioka, Pavel Ivanov

    International Journal of Molecular Sciences　23　(21)　13100-13100　2022/10/28

    Publisher: {MDPI} {AG}

    DOI： 10.3390/ijms232113100 　

    ISSN： 1422-0067

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    <jats:p>Under stress conditions, transfer RNAs (tRNAs) are cleaved by stress-responsive RNases such as angiogenin, generating tRNA-derived RNAs called tiRNAs. As tiRNAs contribute to cytoprotection through inhibition of translation and prevention of apoptosis, the regulation of tiRNA production is critical for cellular stress response. Here, we show that RTCB ligase complex (RTCB-LC), an RNA ligase complex involved in endoplasmic reticulum (ER) stress response and precursor tRNA splicing, negatively regulates stress-induced tiRNA production. Knockdown of RTCB significantly increased stress-induced tiRNA production, suggesting that RTCB-LC negatively regulates tiRNA production. Gel-purified tiRNAs were repaired to full-length tRNAs by RtcB in vitro, suggesting that RTCB-LC can generate full length tRNAs from tiRNAs. As RTCB-LC is inhibited under oxidative stress, we further investigated whether tiRNA production is promoted through the inhibition of RTCB-LC under oxidative stress. Although hydrogen peroxide (H2O2) itself did not induce tiRNA production, it rapidly boosted tiRNA production under the condition where stress-responsive RNases are activated. We propose a model of stress-induced tiRNA production consisting of two factors, a trigger and booster. This RTCB-LC-mediated boosting mechanism may contribute to the effective stress response in the cell.</jats:p>

  11. Selective Cleavage at CCA Ends and Anticodon Loops of tRNAs by Stress-Induced RNases Peer-reviewed

    Yasutoshi Akiyama, Shawn M. Lyons, Marta M. Fay, Yoshihisa Tomioka, Takaaki Abe, Paul J. Anderson, Pavel Ivanov

    Frontiers in Molecular Biosciences　9　2022/03/01

    Publisher: Frontiers Media {SA}

    DOI： 10.3389/fmolb.2022.791094 　

    ISSN： 2296-889X

    eISSN： 2296-889X

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    Stress-induced tRNA cleavage has been implicated in various cellular processes, where tRNA fragments play diverse regulatory roles. Angiogenin (ANG), a member of the RNase A superfamily, induces cleavage of tRNAs resulting in the formation of tRNA-derived stress-induced RNAs (tiRNAs) that contribute to translational reprogramming aiming at cell survival. In addition to cleaving tRNA anticodon loops, ANG has been shown to cleave 3′-CCA termini of tRNAs <italic>in vitro</italic>, although it is not known whether this process occurs in cells. It has also been suggested that tiRNAs can be generated independently of ANG, although the role of other stress-induced RNases in tRNA cleavage is poorly understood. Using gene editing and biochemical approaches, we examined the involvement of ANG in stress-induced tRNA cleavage by focusing on its cleavage of CCA-termini as well as anticodon loops. We show that ANG is not responsible for CCA-deactivation under sodium arsenite (SA) treatment <italic>in cellulo</italic>, and although ANG treatment significantly increases 3′-tiRNA levels in cells, the majority of 3′-tiRNAs retain their 3′-CCA termini. Instead, other RNases can cleave CCA-termini in cells, although with low efficiency. Moreover, in the absence of ANG, other RNases are able to promote the production of tiRNAs in cells. Depletion of RNH1 (an endogenous inhibitor of RNase A superfamily) promotes constitutively-produced tiRNAs and CCA-deactivated tRNAs in cells. Interestingly, SA treatment in RNH1-depleted cells did not increase the amount of tiRNAs or CCA-deactivated tRNAs, suggesting that RNase A superfamily enzymes are largely responsible for SA-induced tRNA cleavage. We show that interplay between stress-induced RNases cause targeting tRNAs in a stress-specific manner <italic>in cellulo</italic>.

  12. tiRNA signaling via stress-regulated vesicle transfer in the hematopoietic niche Peer-reviewed

    Youmna S. Kfoury, Fei Ji, Michael Mazzola, David B. Sykes, Allison K. Scherer, Anthony Anselmo, Yasutoshi Akiyama, Francois Mercier, Nicolas Severe, Konstantinos D. Kokkaliaris, Ting Zhao, Thomas Brouse, Borja Saez, Jefferson Seidl, Ani Papazian, Pavel Ivanov, Michael K. Mansour, Ruslan I. Sadreyev, David T. Scadden

    Cell Stem Cell　28　(12)　2090-2103.e9　2021/12

    Publisher: Elsevier BV

    DOI： 10.1016/j.stem.2021.08.014 　

    ISSN： 1934-5909

  13. In lysate RNA digestion provides insights into the angiogenin’s specificity towards transfer RNAs Peer-reviewed

    Yasutoshi Akiyama, Yoshihisa Tomioka, Takaaki Abe, Paul Anderson, Pavel Ivanov

    RNA Biology　18　(12)　2546-2555　2021/06/04

    Publisher: Informa UK Limited

    DOI： 10.1080/15476286.2021.1930758 　

    ISSN： 1547-6286

    eISSN： 1555-8584

  14. CE-MS-Based Identification of Uremic Solutes Specific to Hemodialysis Patients International-journal Peer-reviewed

    Yasutoshi Akiyama, Koichi Kikuchi, Takafumi Toyohara, Eikan Mishima, Chitose Suzuki, Takehiro Suzuki, Masaaki Nakayama, Yoshihisa Tomioka, Tomoyoshi Soga, Takaaki Abe

    Toxins　13　(5)　324-324　2021/04/30

    Publisher: MDPI AG

    DOI： 10.3390/toxins13050324 　

    eISSN： 2072-6651

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    Uremic toxins are suggested to be involved in the pathophysiology of hemodialysis (HD) patients. However, the profile of uremic solutes in HD patients has not been fully elucidated. In this study using capillary electrophoresis mass spectrometry (CE-MS), we comprehensively quantified the serum concentrations of 122 ionic solutes before and after HD in 11 patients. In addition, we compared the results with those in non-HD patients with chronic kidney disease (CKD) to identify HD patient-specific solutes. We identified 38 solutes whose concentrations were higher in pre-HD than in CKD stage G5. Ten solutes among them did not significantly accumulate in non-HD CKD patients, suggesting that these solutes accumulate specifically in HD patients. We also identified 23 solutes whose concentrations were lower in both pre- and post-HD than in CKD stage G5. The serum levels of 14 solutes among them were not affected by renal function in non-HD patients, suggesting that these solutes tend to be lost specifically in HD patients. Our data demonstrate that HD patients have a markedly different profile of serum uremic solute levels compared to that in non-HD CKD patients. The solutes identified in our study may contribute to the pathophysiology of HD patients.

  15. Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5 International-journal Peer-reviewed

    Yoshitsugu Oikawa, Rumiko Izumi, Masashi Koide, Yoshihiro Hagiwara, Makoto Kanzaki, Naoki Suzuki, Koichi Kikuchi, Tetsuro Matsuhashi, Yukako Akiyama, Mariko Ichijo, Shun Watanabe, Takafumi Toyohara, Takehiro Suzuki, Eikan Mishima, Yasutoshi Akiyama, Yoshiaki Ogata, Chitose Suzuki, Hironori Hayashi, Eiichi N. Kodama, Ken-ichiro Hayashi, Eiji Itoi, Masashi Aoki, Shigeo Kure, Takaaki Abe

    PLOS ONE　15　(12)　e0231064-e0231064　2020/12/02

    Publisher: Public Library of Science (PLoS)

    DOI： 10.1371/journal.pone.0231064 　

    eISSN： 1932-6203

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    Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

  16. Fragmentation of extracellular ribosomes and tRNAs shapes the extracellular RNAome International-journal Peer-reviewed

    Juan Pablo Tosar, Mercedes Segovia, Mauricio Castellano, Fabiana Gámbaro, Yasutoshi Akiyama, Pablo Fagúndez, Álvaro Olivera, Bruno Costa, Tania Possi, Marcelo Hill, Pavel Ivanov, Alfonso Cayota

    Nucleic acids research　2020/08/12

    DOI： 10.1093/nar/gkaa674 　

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    A major proportion of extracellular RNAs (exRNAs) do not copurify with extracellular vesicles (EVs) and remain in ultracentrifugation supernatants of cell-conditioned medium or mammalian blood serum. However, little is known about exRNAs beyond EVs. We have previously shown that the composition of the nonvesicular exRNA fraction is highly biased toward specific tRNA-derived fragments capable of forming RNase-protecting dimers. To solve the problem of stability in exRNA analysis, we developed a method based on sequencing the size exclusion chromatography (SEC) fractions of nonvesicular extracellular samples treated with RNase inhibitors (RI). This method revealed dramatic compositional changes in exRNA population when enzymatic RNA degradation was inhibited. We demonstrated the presence of ribosomes and full-length tRNAs in cell-conditioned medium of a variety of mammalian cell lines. Their fragmentation generates some small RNAs that are highly resistant to degradation. The extracellular biogenesis of some of the most abundant exRNAs demonstrates that extracellular abundance is not a reliable input to estimate RNA secretion rates. Finally, we showed that chromatographic fractions containing extracellular ribosomes are probably not silent from an immunological perspective and could possibly be decoded as damage-associated molecular patterns.

  17. Isolation and initial structure-functional characterization of endogenous tRNA-derived stress-induced RNAs. International-journal Peer-reviewed

    Yasutoshi Akiyama, Prakash Kharel, Takaaki Abe, Paul Anderson, Pavel Ivanov

    RNA biology　17　(8)　1116-1124　2020/08

    DOI： 10.1080/15476286.2020.1732702 　

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    Recent transcriptome-wide studies have identified a diverse pool of transfer RNA (tRNA)-derived RNAs or tRNA-derived fragments (tRFs). Some of these RNAs have been demonstrated to be functional and involved in multiple biological processes ranging from the regulation of gene expression to transgenerational epigenetic inheritance. Post-transcriptional maturation of tRNAs includes various processing events including extensive decoration by various RNA modifications, which are required for correct tRNA folding and stability. Moreover, tRNA modifications determine the pattern and specificity of tRNA cleavage. The major drawbacks of many studies in the field of tRFs are that most of them used synthetic RNAs that closely mimic endogenous tRFs in their sequence, yet lack RNA modification that is found in vivo. Here, we developed a simple method to isolate tRNA-derived stress-induced RNAs (tiRNAs), a specific subset of tRFs. Our approach is scalable, cost-effective and relies on the purification of individual tiRNAs based on a sequence-specific RNA/DNA isolation technique using DNA probes. Our method facilitates functional studies of tiRNAs by addressing how physiological RNA modifications within tRNA fragments affect their biological activities. Here, we report pilot functional studies on selected endogenous tiRNAs, namely tiRNAAla and tiRNAGly. We show that natural 5'-tiRNAAla molecules assemble into G-quadruplex structures, and endogenous 5'-tiRNAGly possesses translation inhibition activity.

  18. eIF4G has intrinsic G-quadruplex binding activity that is required for tiRNA function. International-journal Peer-reviewed

    Shawn M Lyons, Prakash Kharel, Yasutoshi Akiyama, Sandeep Ojha, Dhwani Dave, Vladimir Tsvetkov, William Merrick, Pavel Ivanov, Paul Anderson

    Nucleic acids research　48　(11)　6223-6233　2020/06/19

    DOI： 10.1093/nar/gkaa336 　

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    As cells encounter adverse environmental conditions, such as hypoxia, oxidative stress or nutrient deprivation, they trigger stress response pathways to protect themselves until transient stresses have passed. Inhibition of translation is a key component of such cellular stress responses and mounting evidence has revealed the importance of a class of tRNA-derived small RNAs called tiRNAs in this process. The most potent of these small RNAs are those with the capability of assembling into tetrameric G-quadruplex (G4) structures. However, the mechanism by which these small RNAs inhibit translation has yet to be elucidated. Here we show that eIF4G, the major scaffolding protein in the translation initiation complex, directly binds G4s and this activity is required for tiRNA-mediated translation repression. Targeting of eIF4G results in an impairment of 40S ribosome scanning on mRNAs leading to the formation of eIF2α-independent stress granules. Our data reveals the mechanism by which tiRNAs inhibit translation and demonstrates novel activity for eIF4G in the regulation of translation.

  19. Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease. International-journal Peer-reviewed

    Koichi Kikuchi, Daisuke Saigusa, Yoshitomi Kanemitsu, Yotaro Matsumoto, Paxton Thanai, Naoto Suzuki, Koki Mise, Hiroaki Yamaguchi, Tomohiro Nakamura, Kei Asaji, Chikahisa Mukawa, Hiroki Tsukamoto, Toshihiro Sato, Yoshitsugu Oikawa, Tomoyuki Iwasaki, Yuji Oe, Tomoya Tsukimi, Noriko N Fukuda, Hsin-Jung Ho, Fumika Nanto-Hara, Jiro Ogura, Ritsumi Saito, Shizuko Nagao, Yusuke Ohsaki, Satoshi Shimada, Takehiro Suzuki, Takafumi Toyohara, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yukako Akiyama, Mariko Ichijo, Tetsuro Matsuhashi, Akihiro Matsuo, Yoshiaki Ogata, Ching-Chin Yang, Chitose Suzuki, Matthew C Breeggemann, Jurgen Heymann, Miho Shimizu, Susumu Ogawa, Nobuyuki Takahashi, Takashi Suzuki, Yuji Owada, Shigeo Kure, Nariyasu Mano, Tomoyoshi Soga, Takashi Wada, Jeffrey B Kopp, Shinji Fukuda, Atsushi Hozawa, Masayuki Yamamoto, Sadayoshi Ito, Jun Wada, Yoshihisa Tomioka, Takaaki Abe

    Nature communications　10　(1)　1835-1835　2019/04/23

    DOI： 10.1038/s41467-019-09735-4 　

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    Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.

  20. Stress-induced tRNA cleavage and tiRNA generation in rat neuronal PC12 cells. International-journal Peer-reviewed

    Alaa Elkordy, Eikan Mishima, Kuniyasu Niizuma, Yasutoshi Akiyama, Miki Fujimura, Teiji Tominaga, Takaaki Abe

    Journal of neurochemistry　146　(5)　560-569　2018/09

    DOI： 10.1111/jnc.14321 　

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    Transfer RNA (tRNA) plays a role in stress response programs involved in various pathological conditions including neurological diseases. Under cell stress conditions, intracellular tRNA is cleaved by a specific ribonuclease, angiogenin, generating tRNA-derived fragments or tRNA-derived stress-induced RNA (tiRNA). Generated tiRNA contributes to the cell stress response and has potential cell protective effects. However, tiRNA generation under stress conditions in neuronal cells has not been fully elucidated. To examine angiogenin-mediated tiRNA generation in neuronal cells, we used the rat neuronal cell line, PC12, in combination with analysis of SYBR staining and immuno-northern blotting using anti-1-methyladenosine antibody, which specifically and sensitively detects tiRNA. Oxidative stress induced by arsenite and hydrogen peroxide caused tRNA cleavage and tiRNA generation in PC12 cells. We also demonstrated that oxygen-glucose deprivation, which is an in vitro model of ischemic-reperfusion injury, induced tRNA cleavage and tiRNA generation. In these stress conditions, the amount of generated tiRNA was associated with the degree of morphological cell damage. Time course analysis indicated that generation of tiRNA was prior to severe cell damage and cell death. Angiogenin over-expression did not influence the amount of tiRNA in normal culture conditions; however, it significantly increased tiRNA generation induced by cell stress conditions. Our findings show that angiogenin-mediated tiRNA generation can be induced in neuronal cells by different cell stressors, including ischemia-reperfusion. Additionally, detection of tiRNA could be used as a potential cell damage marker in neuronal cells. Cover Image for this issue: doi: 10.1111/jnc.14191.

  21. Selective embolization therapy for intrarenal artery stenosis causing renovascular hypertension: Efficacy and follow-up renal imaging. International-journal

    Eikan Mishima, Takehiro Suzuki, Kazumasa Seiji, Yasutoshi Akiyama, Hideki Ota, Junichiro Hashimoto, Kei Takase, Takaaki Abe, Sadayoshi Ito

    Journal of clinical hypertension (Greenwich, Conn.)　19　(10)　1028-1031　2017/10

    DOI： 10.1111/jch.13040 　

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    We report the case of a young woman treated with selective renal embolization for renovascular hypertension caused by intrarenal artery stenosis and show follow-up imaging of the treated kidney. An 18-year-old woman had renin-dependent hypertension with intrarenal artery stenosis caused by fibromuscular dysplasia. A middle branch artery was nearly occluded, resulting in segmental renal ischemia with excessive renin secretion. Because our angioplasty attempt for revascularization failed as a result of technical difficulty, we performed selective embolization of the diseased vessel by anhydrous ethanol. The embolization promptly ameliorated hyperreninemia and resistant hypertension without deterioration of renal function. Findings from magnetic resonance imaging showed disappearance of the blood flow in the embolized area corresponding to the ischemic lesion that had been revealed by diffusion-weighted imaging. Thus, selective embolization can be effective in treating renovascular hypertension by intrarenal stenosis for which angioplasty is not feasible. Additionally, renal magnetic resonance imaging is useful for evaluating the causative ischemic lesion and embolized area.

  22. Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach. International-journal

    Eikan Mishima, Shinji Fukuda, Chikahisa Mukawa, Akinori Yuri, Yoshitomi Kanemitsu, Yotaro Matsumoto, Yasutoshi Akiyama, Noriko N Fukuda, Hiroki Tsukamoto, Kei Asaji, Hisato Shima, Koichi Kikuchi, Chitose Suzuki, Takehiro Suzuki, Yoshihisa Tomioka, Tomoyoshi Soga, Sadayoshi Ito, Takaaki Abe

    Kidney international　92　(3)　634-645　2017/09

    DOI： 10.1016/j.kint.2017.02.011 　

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    Gut microbiota is involved in the metabolism of uremic solutes. However, the precise influence of microbiota to the retention of uremic solutes in CKD is obscure. To clarify this, we compared adenine-induced renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles of plasma, feces, and urine using a capillary electrophoresis time-of-flight mass spectrometry-based approach. Mice with renal failure under germ-free conditions demonstrated significant changes in plasma metabolites. Among 183 detected solutes, plasma levels of 11 solutes, including major uremic toxins, were significantly lower in germ-free mice than in SPF mice with renal failure. These 11 solutes were considered microbiota-derived uremic solutes and included indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, γ-guanidinobutyrate, glutarate, 2-hydroxypentanoate, trimethylamine N-oxide, and phenaceturate. Metabolome profiling showed that these solutes were classified into three groups depending on their origins: completely derived from microbiota (indoxyl sulfate, p-cresyl sulfate), derived from both host and microbiota (dimethylglycine), and derived from both microbiota and dietary components (trimethylamine N-oxide). Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Microbiota-derived short-chain fatty acids and efficient amino acid utilization may have a renoprotective effect, and loss of these factors may exacerbate renal damage in germ-free mice with renal failure. Thus, microbiota contributes substantially to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression.

  23. Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases. International-journal

    Tetsuro Matsuhashi, Takeya Sato, Shin-Ichiro Kanno, Takehiro Suzuki, Akihiro Matsuo, Yuki Oba, Motoi Kikusato, Emi Ogasawara, Tai Kudo, Kosuke Suzuki, Osamu Ohara, Hiroko Shimbo, Fumika Nanto, Hiroaki Yamaguchi, Daisuke Saigusa, Yasuno Mukaiyama, Akiko Watabe, Koichi Kikuchi, Hisato Shima, Eikan Mishima, Yasutoshi Akiyama, Yoshitsugu Oikawa, H O Hsin-Jung, Yukako Akiyama, Chitose Suzuki, Mitsugu Uematsu, Masaki Ogata, Naonori Kumagai, Masaaki Toyomizu, Atsushi Hozawa, Nariyasu Mano, Yuji Owada, Setsuya Aiba, Teruyuki Yanagisawa, Yoshihisa Tomioka, Shigeo Kure, Sadayoshi Ito, Kazuto Nakada, Ken-Ichiro Hayashi, Hitoshi Osaka, Takaaki Abe

    EBioMedicine　20　27-38　2017/06

    DOI： 10.1016/j.ebiom.2017.05.016 　

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    Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model "Mitomouse" (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.

  24. A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways. International-journal

    Hisato Shima, Kensuke Sasaki, Takehiro Suzuki, Chikahisa Mukawa, Ten Obara, Yuki Oba, Akihiro Matsuo, Takayasu Kobayashi, Eikan Mishima, Shun Watanabe, Yasutoshi Akiyama, Koichi Kikuchi, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Fumika Nanto, Yukako Akiyama, Hsin-Jung Ho, Chitose Suzuki, Daisuke Saigusa, Atsushi Masamune, Yoshihisa Tomioka, Takao Masaki, Sadayoshi Ito, Ken-Ichiro Hayashi, Takaaki Abe

    Scientific reports　7　(1)　1884-1884　2017/05/15

    DOI： 10.1038/s41598-017-01702-7 　

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    Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis.

  25. RNA biology of angiogenin: Current state and perspectives. International-journal

    Shawn M Lyons, Marta M Fay, Yasutoshi Akiyama, Paul J Anderson, Pavel Ivanov

    RNA biology　14　(2)　171-178　2017/02

    DOI： 10.1080/15476286.2016.1272746 　

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    Angiogenin (ANG) is a secreted ribonuclease best known for its ability to promote formation of blood vessels. Extensive research over many years has elucidated its structure and biophysical properties, although our knowledge of molecular mechanisms underlying ANG-associated biologic processes remains limited. Intriguingly, many of processes require the ribonuclease activity of ANG, thus highlighting the importance of identifying and characterizing RNA targets and intermediates of ANG-mediated endonucleolytic cleavage. While ANG demonstrates ribonuclease activity toward many RNA substrates in vitro, specific target of ANG, namely mature tRNA, was only recently identified in vivo. ANG-mediated tRNA cleavage is an unorthodox manner of generating non-coding RNAs with diverse biologic activities. In addition, the ribonuclease activity of ANG has been reported to be crucial for rRNA transcription. Here we critically discuss various aspects of ANG biology related to its RNase activity and discuss areas in need of further investigation.

  26. Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage. International-journal

    Takehiro Suzuki, Hiroaki Yamaguchi, Motoi Kikusato, Osamu Hashizume, Satoru Nagatoishi, Akihiro Matsuo, Takeya Sato, Tai Kudo, Tetsuro Matsuhashi, Kazutaka Murayama, Yuki Ohba, Shun Watanabe, Shin-Ichiro Kanno, Daichi Minaki, Daisuke Saigusa, Hiroko Shinbo, Nobuyoshi Mori, Akinori Yuri, Miyuki Yokoro, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yoichi Takeuchi, Koichi Kikuchi, Takafumi Toyohara, Chitose Suzuki, Takaharu Ichimura, Jun-Ichi Anzai, Masahiro Kohzuki, Nariyasu Mano, Shigeo Kure, Teruyuki Yanagisawa, Yoshihisa Tomioka, Masaaki Toyomizu, Kohei Tsumoto, Kazuto Nakada, Joseph V Bonventre, Sadayoshi Ito, Hitoshi Osaka, Ken-Ichi Hayashi, Takaaki Abe

    Journal of the American Society of Nephrology : JASN　27　(7)　1925-32　2016/07

    DOI： 10.1681/ASN.2015060623 　

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    Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.

  27. Detection of Segmental Renal Ischemia by Diffusion-Weighted Magnetic Resonance Imaging: Clinical Utility for Diagnosis of Renovascular Hypertension. International-journal

    Eikan Mishima, Koichi Kikuchi, Hideki Ota, Yasutoshi Akiyama, Takehiro Suzuki, Kazumasa Seiji, Junichiro Hashimoto, Kei Takase, Takaaki Abe, Sadayoshi Ito

    Journal of clinical hypertension (Greenwich, Conn.)　18　(4)　364-5　2016/04

    DOI： 10.1111/jch.12675 　

  28. Impact of Small Renal Ischemia in Hypertension Development: Renovascular Hypertension Caused by Small Branch Artery Stenosis. International-journal

    Eikan Mishima, Junichiro Hashimoto, Yasutoshi Akiyama, Hisato Shima, Kazumasa Seiji, Kei Takase, Takaaki Abe, Sadayoshi Ito

    Journal of clinical hypertension (Greenwich, Conn.)　18　(3)　248-9　2016/03

    DOI： 10.1111/jch.12661 　

  29. Posterior reversible encephalopathy syndrome treated with renin-angiotensin system blockade. International-journal

    Eikan Mishima, Junichiro Hashimoto, Yasutoshi Akiyama, Kazumasa Seiji, Kei Takase, Takaaki Abe, Sadayoshi Ito

    Journal of the neurological sciences　355　(1-2)　219-21　2015/08/15

    DOI： 10.1016/j.jns.2015.06.007 　

  30. Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD. International-journal

    Eikan Mishima, Shinji Fukuda, Hisato Shima, Akiyoshi Hirayama, Yasutoshi Akiyama, Yoichi Takeuchi, Noriko N Fukuda, Takehiro Suzuki, Chitose Suzuki, Akinori Yuri, Koichi Kikuchi, Yoshihisa Tomioka, Sadayoshi Ito, Tomoyoshi Soga, Takaaki Abe

    Journal of the American Society of Nephrology : JASN　26　(8)　1787-94　2015/08

    DOI： 10.1681/ASN.2014060530 　

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    The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis-mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.

  31. Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases.

    Takehiro Suzuki, Hiroaki Yamaguchi, Motoi Kikusato, Tetsuro Matsuhashi, Akihiro Matsuo, Takeya Sato, Yuki Oba, Shun Watanabe, Daichi Minaki, Daisuke Saigusa, Hiroko Shimbo, Nobuyoshi Mori, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yoichi Takeuchi, Akinori Yuri, Koichi Kikuchi, Takafumi Toyohara, Chitose Suzuki, Masahiro Kohzuki, Jun-ichi Anzai, Nariyasu Mano, Shigeo Kure, Teruyuki Yanagisawa, Yoshihisa Tomioka, Masaaki Toyomizu, Sadayoshi Ito, Hitoshi Osaka, Ken-ichiro Hayashi, Takaaki Abe

    The Tohoku journal of experimental medicine　236　(3)　225-32　2015/07

    DOI： 10.1620/tjem.236.225 　

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    Mitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in-house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy.

  32. Exonic mutations in the SLC12A3 gene cause exon skipping and premature termination in Gitelman syndrome. International-journal

    Yoichi Takeuchi, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Chitose Suzuki, Takehiro Suzuki, Takayasu Kobayashi, Yoichi Suzuki, Tomohiro Nakayama, Yasuhiro Takeshima, Norma Vazquez, Sadayoshi Ito, Gerardo Gamba, Takaaki Abe

    Journal of the American Society of Nephrology : JASN　26　(2)　271-9　2015/02

    DOI： 10.1681/ASN.2013091013 　

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    A variety of genetic backgrounds cause the loss of function of thiazide-sensitive sodium chloride cotransporter, encoded by SLC12A3, responsible for the phenotypes in Gitelman syndrome. Recently, the phenomenon of exon skipping, in which exonic mutations result in abnormal splicing, has been associated with various diseases. Specifically, mutations in exonic splicing enhancer (ESE) sequences can promote exon skipping. Here, we used a bioinformatics program to analyze 88 missense mutations in the SLC12A3 gene and identify candidate mutations that may induce exon skipping. The three candidate mutations that reduced ESE scores the most were further investigated by minigene assay, and two (p.A356V and p.M672I) caused abnormal splicing in vitro. Furthermore, we identified the p.M672I (c.2016G>A) mutation in a patient with Gitelman syndrome and found that this single nucleotide mutation causes exclusion of exon 16 in the SLC12A3 mRNA transcript. Functional analyses revealed that the protein encoded by the aberrant SLC12A3 transcript does not transport sodium. These results suggest that aberrant exon skipping is one previously unrecognized mechanism by which missense mutations in SLC12A3 can lead to Gitelman syndrome.

  33. Immuno-Northern Blotting: Detection of RNA Modifications by Using Antibodies against Modified Nucleosides. International-journal

    Eikan Mishima, Daisuke Jinno, Yasutoshi Akiyama, Kunihiko Itoh, Shinnosuke Nankumo, Hisato Shima, Koichi Kikuchi, Yoichi Takeuchi, Alaa Elkordy, Takehiro Suzuki, Kuniyasu Niizuma, Sadayoshi Ito, Yoshihisa Tomioka, Takaaki Abe

    PloS one　10　(11)　e0143756　2015

    DOI： 10.1371/journal.pone.0143756 　

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    The biological roles of RNA modifications are still largely not understood. Thus, developing a method for detecting RNA modifications is important for further clarification. We developed a method for detecting RNA modifications called immuno-northern blotting (INB) analysis and herein introduce its various capabilities. This method involves the separation of RNAs using either polyacrylamide or agarose gel electrophoresis, followed by transfer onto a nylon membrane and subsequent immunoblotting using antibodies against modified nucleosides for the detection of specific modifications. We confirmed that INB with the antibodies for 1-methyladenosine (m1A), N6-methyladenosine (m6A), pseudouridine, and 5-methylcytidine (m5C) showed different modifications in a variety of RNAs from various species and organelles. INB with the anti-m5C antibody revealed that the antibody cross-reacted with another modification on DNA, suggesting the application of this method for characterization of the antibody for modified nucleosides. Additionally, using INB with the antibody for m1A, which is a highly specific modification in eukaryotic tRNA, we detected tRNA-derived fragments known as tiRNAs under the cellular stress response, suggesting the application for tracking target RNA containing specific modifications. INB with the anti-m6A antibody confirmed the demethylation of m6A by the specific demethylases fat mass and obesity-associated protein (FTO) and ALKBH5, suggesting its application for quantifying target modifications in separated RNAs. Furthermore, INB demonstrated that the knockdown of FTO and ALKBH5 increased the m6A modification in small RNAs as well as in mRNA. The INB method has high specificity, sensitivity, and quantitative capability, and it can be employed with conventional experimental apparatus. Therefore, this method would be useful for research on RNA modifications and metabolism.

  34. Conformational change in transfer RNA is an early indicator of acute cellular damage. International-journal

    Eikan Mishima, Chisako Inoue, Daisuke Saigusa, Ryusuke Inoue, Koki Ito, Yusuke Suzuki, Daisuke Jinno, Yuri Tsukui, Yosuke Akamatsu, Masatake Araki, Kimi Araki, Ritsuko Shimizu, Haruka Shinke, Takehiro Suzuki, Yoichi Takeuchi, Hisato Shima, Yasutoshi Akiyama, Takafumi Toyohara, Chitose Suzuki, Yoshikatu Saiki, Teiji Tominaga, Shigehito Miyagi, Naoki Kawagisihi, Tomoyoshi Soga, Takayoshi Ohkubo, Kenichi Yamamura, Yutaka Imai, Satohiro Masuda, Venkata Sabbisetti, Takaharu Ichimura, David B Mount, Joseph V Bonventre, Sadayoshi Ito, Yoshihisa Tomioka, Kunihiko Itoh, Takaaki Abe

    Journal of the American Society of Nephrology : JASN　25　(10)　2316-26　2014/10

    DOI： 10.1681/ASN.2013091001 　

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    Tissue damage by oxidative stress is a key pathogenic mechanism in various diseases, including AKI and CKD. Thus, early detection of oxidative tissue damage is important. Using a tRNA-specific modified nucleoside 1-methyladenosine (m1A) antibody, we show that oxidative stress induces a direct conformational change in tRNA structure that promotes subsequent tRNA fragmentation and occurs much earlier than DNA damage. In various models of tissue damage (ischemic reperfusion, toxic injury, and irradiation), the levels of circulating tRNA derivatives increased rapidly. In humans, the levels of circulating tRNA derivatives also increased under conditions of acute renal ischemia, even before levels of other known tissue damage markers increased. Notably, the level of circulating free m1A correlated with mortality in the general population (n=1033) over a mean follow-up of 6.7 years. Compared with healthy controls, patients with CKD had higher levels of circulating free m1A, which were reduced by treatment with pitavastatin (2 mg/d; n=29). Therefore, tRNA damage reflects early oxidative stress damage, and detection of tRNA damage may be a useful tool for identifying organ damage and forming a clinical prognosis.

  35. Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3. International-journal

    Yasutoshi Akiyama, Koichi Kikuchi, Daisuke Saigusa, Takehiro Suzuki, Yoichi Takeuchi, Eikan Mishima, Yasuaki Yamamoto, Ayako Ishida, Daiki Sugawara, Daisuke Jinno, Hisato Shima, Takafumi Toyohara, Chitose Suzuki, Tomokazu Souma, Takashi Moriguchi, Yoshihisa Tomioka, Sadayoshi Ito, Takaaki Abe

    PloS one　8　(7)　e66518　2013

    DOI： 10.1371/journal.pone.0066518 　

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    The accumulated uremic toxins inhibit the expression of various renal transporters and this inhibition may further reduce renal function and subsequently cause the accumulation of uremic toxins. However, the precise mechanism of the nephrotoxicity of uremic toxins on renal transport has been poorly understood. Here we report that indoxyl sulfate, one of the potent uremic toxins, directly suppresses the renal-specific organic anion transporter SLCO4C1 expression through a transcription factor GATA3. The promoter region of SLCO4C1 gene has several GATA motifs, and indoxyl sulfate up-regulated GATA3 mRNA and subsequently down-regulated SLCO4C1 mRNA. Overexpression of GATA3 significantly reduced SLCO4C1 expression, and silencing of GATA3 increased SLCO4C1 expression vice versa. Administration of indoxyl sulfate in rats reduced renal expression of slco4c1 and under this condition, plasma level of guanidinosuccinate, one of the preferable substrates of slco4c1, was significantly increased without changing plasma creatinine. Furthermore, in 5/6 nephrectomized rats, treatment with oral adsorbent AST-120 significantly decreased plasma indoxyl sulfate level and conversely increased the expression of slco4c1, following the reduction of plasma level of guanidinosuccinate. These data suggest that the removal of indoxyl sulfate and blocking its signal pathway may help to restore the SLCO4C1-mediated renal excretion of uremic toxins in CKD.

  36. A metabolomic approach to clarifying the effect of AST-120 on 5/6 nephrectomized rats by capillary electrophoresis with mass spectrometry (CE-MS). International-journal

    Yasutoshi Akiyama, Yoichi Takeuchi, Koichi Kikuchi, Eikan Mishima, Yasuaki Yamamoto, Chitose Suzuki, Takafumi Toyohara, Takehiro Suzuki, Atsushi Hozawa, Sadayoshi Ito, Tomoyoshi Soga, Takaaki Abe

    Toxins　4　(11)　1309-22　2012/11/14

    DOI： 10.3390/toxins4111309 　

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    The oral adsorbent AST-120 is composed of spherical carbon particles and has an adsorption ability for certain small-molecular-weight compounds that accumulate in patients with chronic kidney disease (CKD). So far, very few compounds are known to be adsorbed by AST-120 in vivo. To examine the effect of AST-120 in vivo, we comprehensively evaluated the plasma concentrations of 146 compounds (61 anions and 85 cations) in CKD model rats, with or without four weeks of treatment with AST-120. By capillary electrophoresis with mass spectrometry, we identified 6 anions and 17 cations that were significantly decreased by AST-120 treatment. In contrast, we also identified 2 cations that were significantly increased by AST-120. Among them, 4&#160;anions, apart from indoxyl sulfate and hippurate, and 19 cations were newly identified in this study. The plasma levels of N-acetyl-neuraminate, 4-pyridoxate, 4-oxopentanoate, glycine, &#947;-guanidinobutyrate, N-&#947;-ethylglutamine, allantoin, cytosine, 5-methylcytosine and imidazole-4-acetate were significantly increased in the CKD model compared with the sham-operated group, and were significantly decreased by AST-120 treatment. Therefore, these 10 compounds could be added as uremic compounds that indicate the effect of AST-120 treatment. This study provides useful information not only for identifying the indicators of AST-120, but also for clarifying changes in the metabolic profile by AST-120 treatment in the clinical setting.

  37. Carrier-mediated transport of quercetin conjugates: involvement of organic anion transporters and organic anion transporting polypeptides. International-journal

    Chi Chun Wong, Yasutoshi Akiyama, Takaaki Abe, Jonathan D Lippiat, Caroline Orfila, Gary Williamson

    Biochemical pharmacology　84　(4)　564-70　2012/08/15

    DOI： 10.1016/j.bcp.2012.05.011 　

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    Flavonoids modulate cell signaling and inhibit oxidative enzymes. After oral consumption, they circulate in human plasma as amphiphilic glucuronide or sulfate conjugates, but it is unknown how these physiological metabolites permeate into cells. We examined the mechanisms of uptake of these conjugates into hepatocellular carcinoma (HepG2) cells, and found that uptake of quercetin-3'-O-sulfate was saturable and temperature-dependent, indicating the involvement of carrier-mediated transport. Quercetin-3-O-glucuronide was taken up predominantly via passive diffusion in these cells. Quantitative real-time PCR analysis showed high expression of OATP4C1, followed by OAT2, OAT4 and low expression of OATP1B1 in HepG2 cells, and addition of inhibitors of OATs and OATPs resulted in a significant reduction in quercetin-3'-O-sulfate uptake. The accumulation of quercetin-3'-O-sulfate was further evaluated in HEK293 cells expressing OAT2, OAT4 and OATP4C1. Uptake of quercetin-3'-O-sulfate was 2.3- and 1.4-fold higher in cells expressing OAT4 and OATP4C1 at pH 6.0, respectively, than in control HEK293 cells. siRNA knockdown of OATP4C1 expression in HepG2 cells reduced uptake of quercetin-3'-O-sulfate by ∼40%. This study highlights a role for OATs and OATPs in the cellular uptake of biologically active flavonoid conjugates.

  38. Metabolomic profiling of the autosomal dominant polycystic kidney disease rat model.

    Takafumi Toyohara, Takehiro Suzuki, Yasutoshi Akiyama, Daisuke Yoshihara, Yoichi Takeuchi, Eikan Mishima, Koichi Kikuchi, Chitose Suzuki, Masayuki Tanemoto, Sadayoshi Ito, Shizuko Nagao, Tomoyoshi Soga, Takaaki Abe

    Clinical and experimental nephrology　15　(5)　676-687　2011/10

    DOI： 10.1007/s10157-011-0467-4 　

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    BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease characterized by renal cyst expansion, resulting in renal failure. With the progression of renal damage, the accumulation of uremic compounds is recently reported to subsequently cause further renal damage and hypertension. Finding uremic toxins and sensitive markers for detecting the early stage of ADPKD is necessary to clarify its pathophysiological process and to prevent its progression. The aim of this study was to analyze the profile of uremic retention solutes of ADPKD by capillary electrophoresis-mass spectrometry (CE-MS) using the Han:SPRD rat model. METHODS: Two hundred and ninety-seven cations and 190 anions were comprehensively analyzed by CE-MS in Han:SPRD rats and control rats. RESULTS: We found 21 cations and 19 anions that accumulated significantly in the heterozygous (Cy/+) ADPKD rat model compared with control rats. Among the compounds, increases in 5-methyl-2'-deoxycytidine, glucosamine, ectoine, allantoate, α-hydroxybenzoate, phenaceturate and 3-phenylpropionate and decreases in 2-deoxycytidine, decanoate and 10-hydroxydecanoate were newly identified in the ADPKD Cy/+ rats. CONCLUSION: We identified uremic retention solutes in ADPKD Cy/+ rats. Compounds related to ADPKD could be useful markers for detecting the early stage of ADPKD.

  39. Transcriptional regulation of organic anion transporting polypeptide SLCO4C1 as a new therapeutic modality to prevent chronic kidney disease. International-journal

    Takehiro Suzuki, Takafumi Toyohara, Yasutoshi Akiyama, Yoichi Takeuchi, Eikan Mishima, Chitose Suzuki, Sadayoshi Ito, Tomoyoshi Soga, Takaaki Abe

    Journal of pharmaceutical sciences　100　(9)　3696-707　2011/09

    DOI： 10.1002/jps.22641 　

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    Uremic toxins accumulate in patients with chronic kidney diseases (CKDs) and cause further progression of renal damage and cardiovascular diseases. Recently, it was reported that some of the organic anion transporting polypeptides (OATPs) and the organic anion transporters (OATs) are involved in the renal elimination of uremic toxins. SLCO4C1 is the only OATP expressed at the basolateral side of proximal tubular cells in human kidney, and it mediates the excretion of uremic toxins. The overexpression of human SLCO4C1 in rat kidney promotes the renal excretion of uremic toxins and reduces hypertension, cardiomegaly, and renal inflammation in renal failure. Statins induce SLCO4C1 expression thorough transcriptional factor Aryl hydrocarbon receptor through binding of the xenobiotic responsive element at its promoter region. The administration of statin in a rat renal failure model facilitated the elimination of uremic toxins and mitigated organ damage. In addition, metabolomic analysis of rat renal failure models and patients with CKD by capillary electrophoresis-mass spectrometry is a useful method for identifying new uremic solutes and explores surrogate biomarkers for detecting the progression of early stage CKD.

  40. Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells. International-journal

    Tomokazu Souma, Michiaki Abe, Takashi Moriguchi, Jun Takai, Noriko Yanagisawa-Miyazawa, Eisuke Shibata, Yasutoshi Akiyama, Takafumi Toyohara, Takehiro Suzuki, Masayuki Tanemoto, Takaaki Abe, Hiroshi Sato, Masayuki Yamamoto, Sadayoshi Ito

    Journal of the American Society of Nephrology : JASN　22　(4)　635-48　2011/04

    DOI： 10.1681/ASN.2009111130 　

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    A highly acidic environment surrounds proximal tubular cells as a result of their reabsorption of HCO(3)(-). It is unclear whether this luminal acidity affects proteinuria-induced progression of tubular cell damage. Here, we investigated the contribution of luminal acidity to superoxide (O(2)(·-)) production induced by oleic acid-bound albumin (OA-Alb) in proximal tubular cells. Acidic media significantly enhanced OA-Alb-induced O(2)(·-) production in the HK-2 proximal tubular cell line. Simultaneous treatment with both OA-Alb and acidic media led to phosphorylation of the intracellular pH sensor Pyk2. Highly phosphorylated Pyk2 associated with activation of Rac1, an essential subcomponent of NAD(P)H oxidase. Furthermore, knockdown of Pyk2 with siRNA attenuated the O(2)(·-) production induced by cotreatment with OA-Alb and acid. To assess whether luminal alkalinization abrogates proteinuria-induced tubular damage, we studied a mouse model of protein-overload nephropathy. NaHCO(3) feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O(2)(·-)-induced DNA damage and proximal tubular injury. Overall, these observations suggest that luminal acidity aggravates proteinuria-induced tubular damage and that modulation of this acidic environment may hold potential as a therapeutic target for proteinuric kidney disease.

  41. Metabolomic profiling of uremic solutes in CKD patients. International-journal

    Takafumi Toyohara, Yasutoshi Akiyama, Takehiro Suzuki, Yoichi Takeuchi, Eikan Mishima, Masayuki Tanemoto, Ayako Momose, Naoko Toki, Hiroshi Sato, Masaaki Nakayama, Atsushi Hozawa, Ichiro Tsuji, Sadayoshi Ito, Tomoyoshi Soga, Takaaki Abe

    Hypertension research : official journal of the Japanese Society of Hypertension　33　(9)　944-52　2010/09

    DOI： 10.1038/hr.2010.113 　

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    Early detection and accurate monitoring of patients with chronic kidney disease (CKD) is likely to improve care and decrease the risk of cardiovascular and cerebrovascular diseases. As a new diagnostic tool, we examined the retention of uremic solutes as a simpler, more accurate method to assess renal function. To achieve this, we comprehensively evaluated these solutes in CKD patients. By capillary electrophoresis with mass spectrometry, we found 22 cations and 30 anions that accumulated significantly as the estimated glomerular filtration rate (eGFR) decreased. These compounds included 9 cations and 27 anions that were newly identified in this study. In contrast, we also found 7 cations (2 new) and 5 anions (all new) that decrease significantly as eGFR declines. We evaluated each substance for its suitability to detect early CKD stage. Compounds that are highly correlated with eGFR and whose plasma concentration changed in a manner approximated by the first-degree equation are excellent candidates for detecting CKD and identifying uremic toxins that might aggravate kidney function in the early stage of CKD. These results identify a number of uremic compounds, many of which are novel and which predict worsening renal function. These compounds provide diagnostic information and may be targets for therapies designed to treat the complications of CKD patients.

  42. The HMG-CoA reductase inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides. International-journal

    Michiaki Abe, Takafumi Toyohara, Akiko Ishii, Takehiro Suzuki, Naoya Noguchi, Yasutoshi Akiyama, Hiromi O Shiwaku, Rie Nakagomi-Hagihara, Guodong Zheng, Eisuke Shibata, Tomokazu Souma, Tomohiko Shindo, Hirohito Shima, Yoichi Takeuchi, Eikan Mishima, Masayuki Tanemoto, Tetsuya Terasaki, Tohru Onogawa, Michiaki Unno, Sadayoshi Ito, Shin Takasawa, Takaaki Abe

    Drug metabolism and pharmacokinetics　25　(3)　274-82　2010

    eISSN： 1880-0920

    More details Close

    The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids. Because pravastatin is a water-soluble organic anion, it cannot easily penetrate the lipid bilayer of the cell membrane. As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified, we examined the roles of the organic anion transporter family on pravastatin-treated islet and adipocyte functions. Rat oatp1/slco1a1, oatp2/slco1a4 and oatp3/slco1a5 were expressed in the pancreas, and rat oatp3/slco1a5 was also detected in rat insulinoma cell line INS-1e. Pravastatin was transported not only by oatp1/slco1a1 and oatp2/slco1a4, but also by rat oatp3/slco1a5. Pravastatin uptake into INS-1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin, both of which are known to inhibit oatp family-mediated uptake. In addition, pravastatin enhanced the glucose-stimulated insulin secretion from INS-1e cells. When fat-loaded db/db mice were treated with pravastatin, glucose intolerance and insulin resistance were prevented. In addition, insulin secretion from isolated islets was enhanced by pravastatin. These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat/glucose conditions.

  43. SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation. International-journal

    Takafumi Toyohara, Takehiro Suzuki, Ryo Morimoto, Yasutoshi Akiyama, Tomokazu Souma, Hiromi O Shiwaku, Yoichi Takeuchi, Eikan Mishima, Michiaki Abe, Masayuki Tanemoto, Satohiro Masuda, Hiroaki Kawano, Koji Maemura, Masaaki Nakayama, Hiroshi Sato, Tsuyoshi Mikkaichi, Hiroaki Yamaguchi, Shigefumi Fukui, Yoshihiro Fukumoto, Hiroaki Shimokawa, Ken-ichi Inui, Tetsuya Terasaki, Junichi Goto, Sadayoshi Ito, Takanori Hishinuma, Isabelle Rubera, Michel Tauc, Yoshiaki Fujii-Kuriyama, Hikaru Yabuuchi, Yoshinori Moriyama, Tomoyoshi Soga, Takaaki Abe

    Journal of the American Society of Nephrology : JASN　20　(12)　2546-55　2009/12

    DOI： 10.1681/ASN.2009070696 　

    More details Close

    Hypertension in patients with chronic kidney disease (CKD) strongly associates with cardiovascular events. Among patients with CKD, reducing the accumulation of uremic toxins may protect against the development of hypertension and progression of renal damage, but there are no established therapies to accomplish this. Here, overexpression of human kidney-specific organic anion transporter SLCO4C1 in rat kidney reduced hypertension, cardiomegaly, and inflammation in the setting of renal failure. In addition, SLCO4C1 overexpression decreased plasma levels of the uremic toxins guanidino succinate, asymmetric dimethylarginine, and the newly identified trans-aconitate. We found that xenobiotic responsive element core motifs regulate SLCO4C1 transcription, and various statins, which act as inducers of nuclear aryl hydrocarbon receptors, upregulate SLCO4C1 transcription. Pravastatin, which is cardioprotective, increased the clearance of asymmetric dimethylarginine and trans-aconitate in renal failure. These data suggest that drugs that upregulate SLCO4C1 may have therapeutic potential for patients with CKD.

  44. [Pathophysiology of cardiorenal interaction].

    Yasutoshi Akiyama

    Nihon rinsho. Japanese journal of clinical medicine　2008/09/01

    More details Close

    In the renal circulation, the afferent arterioles leading to juxtamedullary glomeruli are anatomically under high pressure load in order to reduce the high arterial pressure and keep the pressure of the following glomeruli at about 50 mmHg. Because of the pressure overload, it is possible that vascular injury begins in the afferent arterioles of juxtamedullary glomeruli. We call such high pressure-loaded vessels branching directly from relatively large vessels 'strain vessels'. Coronary arteries and penetrating cerebral arteries are also strain vessels. They are also susceptible to pressure-induced injury. This review presents a hypothesis that microalbuminuria reflects the early stage of vascular injury, especially strain vessels' injury, and that strain vessels' injury connects chronic kidney disease with the risk of cardiovascular disease.

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Misc. 113

  1. tRNAHis特異的酵素THG1Lが細胞のストレス応答に与える影響の検討

    清水珠生, 秋山泰利, 松本洋太郎, 富岡佳久

    日本薬学会東北支部大会講演要旨集　62nd　2023

  2. ミトコンドリア病の病態解明に向けたtRNA特異的抽出法の開発

    中川翔平, 渡邉麻友香, 山田明日香, 秋山泰利, 松本洋太郎, 富岡佳久

    日本薬学会東北支部大会講演要旨集　62nd　2023

  3. 糖尿病性腎臓病評価法に用いる蛍光標識フェニルサルフェートの合成

    熊谷知大, 小田垣水晶, 秋山泰利, 松本洋太郎, 塚本宏樹, 金光祥臣, 富岡佳久

    日本薬学会東北支部大会講演要旨集　62nd　2023

  4. 尿毒素フェニル硫酸はインスリン分泌を刺激し糖尿病性腎症におけるインスリン抵抗性を惹起する

    頓宮慶泰, 笠原朋子, 川邊千陽, 鈴木健新, 菊地晃一, 三瀬広記, 鯨井涼太, 松本洋太郎, 秋山泰利, 渡邉駿, 豊原敬文, 鈴木健弘, 和田淳, 富岡佳久, 田中哲洋, 阿部高明

    日本腎臓学会誌(Web)　65　(3)　2023

    ISSN： 1884-0728

  5. 誘導体化を用いたLC-MS/MSアルギニン代謝物定量系の構築

    浦里真莉菜, 鯨井涼太, 秋山泰利, 松本洋太郎, 渡邉駿, 阿部高明, 富岡佳久

    日本薬学会東北支部大会講演要旨集　62nd　2023

  6. 糖尿病性腎症におけるインスリン分泌促進とインスリン抵抗性亢進の原因に尿毒素フェニル硫酸が存在する

    頓宮慶泰, 笠原朋子, 川邊千陽, 鈴木健新, 菊地晃一, 菊地晃一, 三瀬広記, 鯨井涼太, 松本洋太郎, 秋山泰利, 鈴木千登世, 渡邉駿, 渡邉駿, 豊原敬文, 豊原敬文, 鈴木健弘, 鈴木健弘, 和田淳, 富岡佳久, 田中哲弘, 阿部高明, 阿部高明

    糖尿病(Web)　66　(Suppl)　2023

    ISSN： 1881-588X

  7. Phenyl sulfate facilitates insulin secretion and exacerbates insulin resistance in diabetic kidney disease

    頓宮慶泰, 菊地晃一, 鈴木健新, 三瀬広記, 和田淳, 秋山泰利, 那谷耕司, 鯨井涼太, 松本洋太郎, 富岡佳久, 渡邉駿, 豊原敬文, 鈴木健弘, 田中哲弘, 阿部高明

    日本高血圧学会総会プログラム・抄録集(CD-ROM)　44th　2022

  8. 修飾核酸特異的抗体を用いたストレス反応性RNA修飾のスクリーニング

    竹中慶香, 秋山泰利, 松本洋太郎, 富岡佳久

    日本薬学会東北支部大会講演要旨集　60th　2021

  9. 標的分子を内在化し分解誘導する二重特異性抗体の機能評価

    西田健人, 山崎晶貴, 秋山泰利, 松本洋太郎, 富岡佳久, 益子高

    日本薬学会東北支部大会講演要旨集　60th　2021

  10. 細胞外小胞を介したCD73のがん病態に与える影響の評価

    山田愛梨香, 秋山泰利, 松本洋太郎, 富岡佳久

    日本薬学会東北支部大会講演要旨集　60th　2021

  11. 透析患者特異的な病態に関する尿毒素の同定

    秋山 泰利, 阿部 高明

    日本透析医会雑誌　33　(3)　514-520　2018/12

    Publisher: (公社)日本透析医会

    ISSN： 0914-7136

  12. ミトコンドリア病新規治療薬Mitochonic Acid(MA)-5は腎障害を有するミトコンドリア病患者に対する新規治療薬となる

    松橋 徹郎, 鈴木 健弘, 及川 善嗣, 秋山 由雅子, 菊地 晃一, 島 久登, 三島 英換, 秋山 泰利, 鈴木 千登世, 呉 繁夫, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　59　(3)　236-236　2017/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  13. Indole analogs have novel therapeutic effects on mitochondrial diseases

    Tetsuro Matsuhashi, Takehiro Suzuki, Akihiro Matsuo, Yuuki Oba, Kousuke Suzuki, Kouichi Kikuchi, Hisato Shima, Youichi Takeuchi, Eikan Mishima, Yasutoshi Akiyama, Chitose Suzuki, Takeya Sato, Teruyuki Yanagisawa, Kenichiro Hayashi, Hitoshi Osaka, Kazuto Nakada, Takaaki Abe

    MITOCHONDRION　31　96-97　2016/11

    ISSN： 1567-7249

    eISSN： 1872-8278

  14. ミトコンドリア病の新規治療薬Michonic acid-5(MA-5)はミトコンドリア機能不全と腎機能不全を改善する

    鈴木 健弘, 松橋 徹郎, 菊地 晃一, 島 久登, 竹内 陽一, 三島 英換, 秋山 泰利, 鈴木 千登世, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　58　(3)　277-277　2016/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  15. 抗TNF-α作用と抗TGF-β1作用を有する化合物の発見と臨床応用

    島 久登, 鈴木 健弘, 菊地 晃一, 三島 英換, 秋山 泰利, 鈴木 千登世, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　58　(3)　365-365　2016/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  16. ミトコンドリア病の新規治療薬Michonic acid-5(MA-5)

    松橋 徹郎, 鈴木 健弘, 菊地 晃一, 島 久登, 三島 英換, 秋山 泰利, 小坂 仁, 呉 繁夫, 阿部 高明

    日本内科学会雑誌　105　(Suppl.)　183-183　2016/02

    Publisher: (一社)日本内科学会

    ISSN： 0021-5384

    eISSN： 1883-2083

  17. 粥状硬化性腎動脈狭窄症に対するステント治療の有効性と予後因子

    鈴木 健弘, 藤原 昌彦, 秋山 泰利, 三島 英換, 竹内 陽一, 鈴木 千登世, 横井 良明, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　38回　358-358　2015/10

    Publisher: (NPO)日本高血圧学会

  18. PTRA時の末梢塞栓により治療後に高血圧が残存した線維筋性異形成による腎血管性高血圧の一例

    向山 靖乃, 三島 英換, 秋山 泰利, 菊地 晃一, 鈴木 健弘, 橋本 潤一郎, 阿部 高明, 伊藤 貞嘉

    日本腎臓学会誌　57　(6)　998-998　2015/08

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  19. 被災地での生活習慣介入が血清可溶性(プロ)レニン受容体濃度に及ぼす影響

    秋山 泰利, 阿部 高明, 伊藤 貞嘉, 清元 秀泰

    日本高血圧学会臨床高血圧フォーラムプログラム・抄録集　4回　142-142　2015/05

    Publisher: (NPO)日本高血圧学会

  20. 両側腎動脈狭窄を合併する悪性高血圧の治療におけるACE阻害薬の必要性

    三島 英換, 菊地 晃一, 秋山 泰利, 島 久登, 橋本 潤一郎, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会臨床高血圧フォーラムプログラム・抄録集　4回　149-149　2015/05

    Publisher: (NPO)日本高血圧学会

  21. CE-MSによる透析患者に特異的な尿毒素の網羅的探索

    秋山 泰利, 菊地 晃一, 島 久登, 三島 英換, 中山 昌明, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本透析医学会雑誌　48　(Suppl.1)　753-753　2015/05

    Publisher: (一社)日本透析医学会

    ISSN： 1340-3451

    eISSN： 1883-082X

  22. 尿毒素蓄積における腸内細菌叢の関与 無菌腎不全マウスとCE-TOFMSを用いた解析

    三島 英換, 福田 真嗣, 秋山 泰利, 島 久登, 菊地 晃一, 鈴木 健弘, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　57　(3)　472-472　2015/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  23. ルビプロストンの腸内環境改善を介したアデニンCKDモデルにおける腎障害抑制効果

    三島 英換, 福田 真嗣, 秋山 泰利, 島 久登, 菊地 晃一, 鈴木 健弘, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　57　(3)　472-472　2015/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  24. ベラプロストは腎不全時腎機能改善と尿毒症物質減少をもたらす

    大庭 悠貴, 松山 由香, 鈴木 康介, 宇留野 晃, 秋山 泰利, 三島 英換, 島 久登, 菊地 晃一, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　57　(3)　487-487　2015/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  25. 被災地での生活習慣介入が血清可溶性(プロ)レニン受容体濃度に及ぼす影響

    秋山 泰利, 阿部 高明, 伊藤 貞嘉, 清元 秀泰

    日本腎臓学会誌　57　(3)　510-510　2015/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  26. GDF-15は急性腎障害およびCKDの腎機能障害の早期診断マーカー

    佐々木 駿, 小原 万妃, 櫻田 冴響, 秋山 泰利, 三島 英換, 島 久登, 菊地 晃一, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　57　(3)　540-540　2015/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  27. 抗炎症作用と抗線維化作用を有する化合物の探索と臨床応用

    島 久登, 菊地 晃一, 松橋 徹郎, 三島 英換, 秋山 泰利, 鈴木 健弘, 鈴木 千登世, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　57　(3)　569-569　2015/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  28. ギテルマン症候群の新たな発症メカニズムとしてのエクソンスキッピングの発見

    竹内 陽一, 島 久登, 三島 英換, 秋山 泰利, 鈴木 千登世, 伊藤 貞嘉, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　37回　328-328　2014/10

    Publisher: (NPO)日本高血圧学会

  29. 【腎臓病のすべて】腎臓病の治療薬の使い方 尿毒素吸着療法

    秋山 泰利, 阿部 高明

    医学のあゆみ　249　(9)　889-894　2014/05

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  30. 尿毒素から見たCKDの病態と治療 メタゲノムとメタボローム解析による腎不全時の腸内環境変化の検討

    三島 英換, 福田 真嗣, 秋山 泰利, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本腎臓学会誌　56　(3)　256-256　2014/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  31. エクソンスキッピングギテルマン症候群の新たな発症メカニズム

    竹内 陽一, 島 久登, 三島 英換, 秋山 泰利, 中山 智祥, 竹島 泰弘, Gamba G, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　56　(3)　316-316　2014/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  32. 虚血ストレスに対するインドール・インドキシル化合物の保護効果の検討

    渡邉 駿, 大庭 悠貴, 松尾 明大, 島 久登, 竹内 陽一, 三島 英換, 秋山 泰利, 鈴木 千登世, 鈴木 健弘, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　56　(3)　322-322　2014/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  33. ミトコンドリア腎症患者培養線維芽細胞を用いたミトコンドリア機能改善薬物の探索

    松尾 明大, 大庭 悠貴, 渡邉 駿, 島 久登, 竹内 陽一, 三島 英換, 秋山 泰利, 鈴木 千登世, 鈴木 健弘, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　56　(3)　325-325　2014/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  34. 腎線維化、炎症改善効果を有する化合物の探索と臨床応用

    島 久登, 鈴木 健弘, 竹内 陽一, 三島 英換, 秋山 泰利, 鈴木 千登世, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　56　(3)　345-345　2014/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  35. エリスロポエチン産生増強化合物の作用機序の解明

    大庭 悠貴, 渡邉 駿, 松尾 明大, 島 久登, 竹内 陽一, 三島 英換, 秋山 泰利, 鈴木 千登世, 鈴木 健弘, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　56　(3)　398-398　2014/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  36. 【活性酸素-基礎から病態解明・制御まで】疾患病態・臨床編 慢性腎臓病と酸化ストレス

    秋山 泰利, 阿部 高明

    医学のあゆみ　247　(9)　901-906　2013/11

    Publisher: 医歯薬出版(株)

    ISSN： 0039-2359

  37. 【尿細管トランスポーターの機能制御と疾患治療-トピックス】尿毒素の輸送とCKD

    秋山 泰利, 阿部 高明

    腎と骨代謝　26　(3)　223-229　2013/07

    Publisher: (株)日本メディカルセンター

    ISSN： 0914-5265

    eISSN： 2433-2496

  38. 腎動脈狭窄症32名に対する治療とその予後

    鈴木 雄介, 鈴木 健弘, 秋山 泰利, 橋本 潤一郎, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会臨床高血圧フォーラムプログラム・抄録集　2回　140-140　2013/05

    Publisher: (NPO)日本高血圧学会

  39. CE-MSを用いた透析患者の病態に特異的な尿毒症物質の同定

    秋山 泰利, 竹内 陽一, 三島 英換, 鈴木 健弘, 曽我 朋義, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　55　(3)　432-432　2013/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  40. tRNAの挙動検知はDNAダメージよりも早期の虚血組織障害マーカーとなる

    三島 英換, 井上 稚沙子, 三枝 大輔, 竹内 陽一, 秋山 泰利, 鈴木 健弘, 富岡 久佳, 伊藤 邦彦, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　55　(3)　296-296　2013/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  41. 【動脈硬化とアフェレシス】動脈硬化と尿毒症

    秋山 泰利, 阿部 高明

    日本アフェレシス学会雑誌　32　(1)　34-42　2013/02

    Publisher: (一社)日本アフェレシス学会

    ISSN： 1340-5888

  42. 心-腎連関

    秋山 泰利, 阿部 高明, 伊藤 貞嘉

    血管　36　(1)　18-18　2013/01

    Publisher: 日本心脈管作動物質学会

    ISSN： 0911-4637

  43. Basic nephrology 分子生物学 CKDにおけるトランスポーター発現変化メカニズム

    秋山 泰利, 鈴木 健弘, 阿部 高明

    Annual Review腎臓　2013　109-117　2013/01

    Publisher: (株)中外医学社

  44. アンジオテンシンType1受容体ブロッカーは慢性腎臓病患者においてeGERと相関せずにメチルグリオキサールを減少させる

    鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 伊藤 貞嘉, 中村 司, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　35回　455-455　2012/09

    Publisher: (NPO)日本高血圧学会

  45. アンジオテンシンtype1受容体ブロッカーとチアゾリジンは尿毒素排泄トランスポーターの発現を制御する

    鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 伊藤 貞嘉, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　35回　459-459　2012/09

    Publisher: (NPO)日本高血圧学会

  46. 慢性腎臓病患者のスタチンによる腎保護効果の検討

    青木 靖子, 鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 佐藤 博, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　54　(6)　718-718　2012/08

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  47. ARBは慢性腎臓病患者においてeGFRと相関せずメチルグリオキサールを減少させる

    池之内 初, 鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 伊藤 貞嘉, 中村 司, 阿部 高明

    日本腎臓学会誌　54　(6)　719-719　2012/08

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  48. 尿毒症物質によるエリスロポエチン産生低下の発症機序の解明

    秋山 泰利, 鈴木 健弘, 豊原 敬文, 竹内 陽一, 三島 英換, 佐藤 博, 伊藤 貞義, 阿部 高明

    日本内分泌学会雑誌　88　(1)　374-374　2012/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  49. ARBは慢性腎臓病患者においてeGFRと相関せずメチルグリオキサールを減少させる

    鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 伊藤 貞嘉, 中村 司, 阿部 高明

    日本腎臓学会誌　54　(3)　253-253　2012/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  50. 5-アミノレブリン酸は炎症時のEpo産生能低下を改善する

    一条 貞満, 秋山 泰利, 鈴木 健弘, 鈴木 千登勢, 古山 和道, 三島 英換, 竹内 陽一, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　54　(3)　320-320　2012/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  51. ARBとチアゾリジンは尿毒素排泄トランスポーターの発現を制御する

    鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　54　(3)　322-322　2012/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  52. SLCO4C1トランスポーター発現低下による尿毒症物質蓄積の悪循環の解明と新規治療法の開発

    秋山 泰利, 鈴木 健弘, 三島 英換, 竹内 陽一, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　54　(3)　322-322　2012/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  53. アンジオテンシンtype1受容体ブロッカーとチアゾリジンは尿毒素排泄トランスポーターの発現を制御する

    秋山 泰利, 鈴木 健弘, 竹内 陽一, 三島 英換, 伊藤 貞嘉, 阿部 高明

    日本高血圧学会臨床高血圧フォーラムプログラム・抄録集　1回　122-122　2012/04

    Publisher: (NPO)日本高血圧学会

  54. アンジオテンシンtype1受容体ブロッカーは慢性腎臓病患者においてeGFRと相関せずメチルグリオキサールを減少させる

    鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 伊藤 貞嘉, 中村 司, 阿部 高明

    日本高血圧学会臨床高血圧フォーラムプログラム・抄録集　1回　141-141　2012/04

    Publisher: (NPO)日本高血圧学会

  55. スタチンによる尿毒症物質排泄トランスポーター発現制御と腎不全治療

    鈴木 健弘, 豊原 敬文, 秋山 泰利, 竹内 陽一, 三島 英換, 佐藤 博, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    Therapeutic Research　33　(2)　201-203　2012/02

    Publisher: ライフサイエンス出版(株)

    ISSN： 0289-8020

  56. 慢性腎臓病患者のスタチンによる腎保護効果の検討

    鈴木健弘, 秋山泰利, 竹内陽一, 三島英換, 三枝大輔, 佐藤博, 伊藤貞嘉, 阿部高明, 阿部高明, 阿部高明

    Therapeutic Research　33　(8)　1196-1199　2012

    Publisher: ライフサイエンス出版(株)

    ISSN： 0289-8020

  57. 尿毒症物質による尿毒症物質排泄トランスポーターSLCO4C1の転写制御と排泄促進の意義

    鈴木 健弘, 豊原 敬文, 秋山 泰利, 竹内 陽一, 三島 英換, 佐藤 博, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　34回　422-422　2011/10

    Publisher: (NPO)日本高血圧学会

  58. 【腎不全の最近の動向と阻止対策-原疾患とメカニズムに基づいた治療法の新たな展開】補助療法 スタチンによるCKDの治療

    秋山 泰利, 阿部 高明

    カレントテラピー　29　(8)　741-745　2011/08

    Publisher: (株)ライフメディコム

    ISSN： 0287-8445

  59. 【透析患者と血圧異常】新規尿毒素トランスアコニット酸

    秋山 泰利, 阿部 高明

    臨床透析　27　(9)　1248-1249　2011/08

    Publisher: (株)日本メディカルセンター

    ISSN： 0910-5808

    eISSN： 2433-247X

  60. 尿細管ヘンレ上行脚Na+輸送を制御する新たな機構の解明

    三島 英換, 竹内 陽一, 秋山 泰利, 鈴木 健弘, 阿部 高明, 種本 雅之, 内田 俊也, 伊藤 貞嘉

    日本腎臓学会誌　53　(3)　367-367　2011/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  61. 尿毒症物質による尿毒症物質排泄トランスポーターSLCO4C1の転写制御の意義

    鈴木 健弘, 豊原 敬文, 秋山 泰利, 竹内 陽一, 三島 英換, 鈴木 千登世, 山口 浩明, 曽我 朋義, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　53　(3)　385-385　2011/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  62. 尿毒症物質はEpo受容体発現量を低下させEpo抵抗性を惹起する

    山本 恭彰, 秋山 泰利, 鈴木 健弘, 竹内 陽一, 三島 英換, 鈴木 千登世, 伊藤 貞嘉, 曽我 朋義, 小松 則夫, 阿部 高明

    日本腎臓学会誌　53　(3)　386-386　2011/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  63. クレメジン投与により低下する尿毒症物質の網羅的探索

    竹内 陽一, 三島 英換, 秋山 泰利, 鈴木 健弘, 鈴木 千登世, 曽我 朋義, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌　53　(3)　432-432　2011/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  64. スタチンによる尿毒書物質排泄トランスポーターの発現制御と腎不全治療

    鈴木 健弘, 豊原 敬文, 秋山 泰利, 竹内 陽一, 三島 英換, 佐藤 博, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本内分泌学会雑誌　87　(1)　287-287　2011/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  65. 尿細管管腔内アルカリ化は蛋白尿による近位尿細管細胞酸化ストレスを、Pyk2経路を介して改善させる

    相馬 友和, 阿部 倫明, 森口 尚, 高井 淳, 秋山 泰利, 豊原 敬文, 鈴木 健弘, 種本 雅之, 阿部 高明, 山本 雅之, 伊藤 貞嘉

    血管　34　(1)　32-33　2011/01

    Publisher: 日本心脈管作動物質学会

    ISSN： 0911-4637

  66. トランスポーター研究の臨床薬理 尿細管排泄機構と尿毒症物質 トランスポーター発現制御による腎不全治療

    鈴木 健弘, 豊原 敬文, 秋山 泰利, 竹内 陽一, 三島 英換, 中山 昌明, 佐藤 博, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    臨床薬理　41　(Suppl.)　S139-S139　2010/11

    Publisher: (一社)日本臨床薬理学会

    ISSN： 0388-1601

    eISSN： 1882-8272

  67. Metabolomic profiling of uremic solutes in CKD patients (vol 33, pg 945, 2010)

    Takafumi Toyohara, Yasutoshi Akiyama, Takehiro Suzuki, Yoichi Takeuchi, Eikan Mishima, Masayuki Tanemoto, Ayako Momose, Naoko Toki, Hiroshi Sato, Masaaki Nakayama, Atsushi Hozawa, Ichiro Tsuji, Sadayoshi Ito, Tomoyoshi Soga, Takaaki Abe

    HYPERTENSION RESEARCH　33　(10)　1089-1089　2010/10

    DOI： 10.1038/hr.2010.158 　

    ISSN： 0916-9636

  68. トランスポーターを介したスタチンによる尿毒症性物質排泄強化による新たな慢性腎臓病治療

    豊原 敬文, 鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 種本 雅之, 中山 昌明, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    Diabetes Frontier　21　(5)　631-632　2010/10

    Publisher: (株)メディカルレビュー社

    ISSN： 0915-6593

  69. 尿毒症物質排泄を担う腎臓特異的有機アニオントランスポーターSLCO4C1のスタチンによる発現誘導効果の検討

    鈴木 健弘, 豊原 敬文, 秋山 泰利, 竹内 陽一, 三島 英換, 種本 雅之, 中山 昌明, 佐藤 博, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　33回　250-250　2010/10

    Publisher: (NPO)日本高血圧学会

  70. CKD患者における尿毒症物質の解析

    秋山 泰利, 鈴木 健弘, 豊原 敬文, 竹内 陽一, 三島 英換, 種本 雅之, 中山 昌明, 佐藤 博, 寳澤 篤, 辻 一郎, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　33回　365-365　2010/10

    Publisher: (NPO)日本高血圧学会

  71. 動脈硬化性腎動脈狭窄を発見する為の予測因子の検討

    三島 英換, 齋藤 陽孝, 竹内 陽一, 秋山 泰利, 豊原 敬文, 鈴木 健弘, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　33回　396-396　2010/10

    Publisher: (NPO)日本高血圧学会

  72. スタチンによる尿毒症物質排泄のメカニズムとその臨床応用

    豊原 敬文, 鈴木 健弘, 秋山 泰利, 竹内 陽一, 三島 英換, 種本 雅之, 中山 昌明, 佐藤 博, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    Therapeutic Research　31　(9)　1221-1223　2010/09

    Publisher: ライフサイエンス出版(株)

    ISSN： 0289-8020

  73. CKD患者と腎不全ラットにおける腎不全物質の網羅的解析

    豊原 敬文, 秋山 泰利, 鈴木 健弘, 竹内 陽一, 三島 英換, 種本 雅之, 佐藤 博, 中山 昌明, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本透析医学会雑誌　43　(Suppl.1)　363-363　2010/05

    Publisher: (一社)日本透析医学会

    ISSN： 1340-3451

    eISSN： 1883-082X

  74. CE-MSを用いた血液透析前後の尿毒症物質除去効率の網羅的解析

    秋山 泰利, 竹内 陽一, 三島 英換, 豊原 敬文, 鈴木 健弘, 種本 雅之, 中山 昌明, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本透析医学会雑誌　43　(Suppl.1)　800-800　2010/05

    Publisher: (一社)日本透析医学会

    ISSN： 1340-3451

    eISSN： 1883-082X

  75. 腎臓特異的有機アニオントランスポーターSLCO4C1による腎不全物質排泄促進を介した高血圧と腎内炎症の改善

    鈴木 健弘, 豊原 敬文, 秋山 泰利, 竹内 陽一, 三島 英換, 種本 雅之, 中山 昌明, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本腎臓学会誌　52　(3)　281-281　2010/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  76. キャピラリー電気泳動質量分析により同定された新規ヒト腎不全物質18種類の毒性と酸化ストレス惹起

    菊地 晃一, 豊原 敬文, 秋山 泰利, 鈴木 健弘, 竹内 陽一, 三島 英換, 種本 雅之, 佐藤 博, 中山 昌明, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本腎臓学会誌　52　(3)　281-281　2010/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  77. CKD患者の尿毒症物質と早期診断マーカーの網羅的解析

    豊原 敬文, 秋山 泰利, 鈴木 健弘, 竹内 陽一, 三島 英換, 種本 雅之, 佐藤 博, 中山 昌明, 寳澤 篤, 辻 一郎, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本腎臓学会誌　52　(3)　340-340　2010/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  78. CE-MSを用いた血液透析前後の尿毒症物質除去効率の網羅的解析

    秋山 泰利, 竹内 陽一, 三島 英換, 豊原 敬文, 鈴木 健弘, 種本 雅之, 中山 昌明, 伊藤 貞嘉, 曽我 朋義, 阿部 高明

    日本腎臓学会誌　52　(3)　378-378　2010/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  79. ADPKDモデルラットにおける腎不全物質の網羅的解析

    豊原 敬文, 秋山 泰利, 鈴木 健弘, 竹内 陽一, 三島 英換, 種本 雅之, 伊藤 貞嘉, 長尾 枝澄香, 曽我 朋義, 阿部 高明

    日本腎臓学会誌　52　(3)　396-396　2010/05

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  80. Statin-inducible uremic toxin transporter prevents hypertension, renal function and inflammation

    Takehiro Suzuki, Takafumi Toyohara, Yasutoshi Akiyama, Masayuki Tanemoto, Sadayoshi Ito, Tomoyoshi Soga, Takaaki Abe

    ENDOCRINE JOURNAL　57　S330-S331　2010/03

    ISSN： 0918-8959

  81. Acidification Aggravates Fatty Acid-Bound Albumin-Induced Superoxide Production in Renal Proximal Tubular Cells Through Activation of Pyk2 Pathways

    Tomokazu Souma, Michiaki Abe, Yasutoshi Akiyama, Takafumi Toyohara, Shiwaku O. Hiromi, Takehiro Suzuki, Masayuki Tanemoto, Takaaki Abe, Sadayoshi Ito

    HYPERTENSION　54　(4)　E84-E84　2009/10

    ISSN： 0194-911X

  82. 尿細管管腔内酸性化は脂肪酸結合アルブミンによる近位尿細管細胞からの活性酸素産生を増悪させる

    相馬 友和, 阿部 倫明, 秋山 泰利, 豊原 敬文, 塩飽 博美, 竹内 陽一, 三島 英換, 鈴木 健弘, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　32回　172-172　2009/10

    Publisher: (NPO)日本高血圧学会

  83. ヒト腎臓特異的有機アニオントランスポーターSLCO4C1の転写活性調節と臨床応用

    鈴木 健弘, 豊原 敬文, 秋山 泰利, 相馬 友和, 竹内 陽一, 三島 英換, 阿部 倫明, 種本 雅之, 伊藤 貞嘉, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　32回　236-236　2009/10

    Publisher: (NPO)日本高血圧学会

  84. 狭窄部血行動態指標と血行再建術による降圧効果の動脈硬化性腎動脈狭窄での検討

    種本 雅之, 竹内 陽一, 三島 英換, 相馬 友和, 秋山 泰利, 豊原 敬文, 鈴木 健弘, 阿部 倫明, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　32回　313-313　2009/10

    Publisher: (NPO)日本高血圧学会

  85. スタチンによる血圧降下作用機序の解析

    豊原 敬文, 秋山 泰利, 竹内 陽一, 三島 英換, 相馬 友和, 鈴木 健弘, 阿部 倫明, 種本 雅之, 曽我 朋義, 伊藤 貞嘉, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　32回　323-323　2009/10

    Publisher: (NPO)日本高血圧学会

  86. 腎動脈ステント留置後再狭窄の治療適応判定における腎動脈エコーの有用性

    竹内 陽一, 三島 英換, 秋山 泰利, 豊原 敬文, 鈴木 健弘, 阿部 倫明, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本腎臓学会誌　51　(6)　692-692　2009/08

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  87. ミネラルコルチコイドによるイオン輸送制御の分子機構

    種本 雅之, 豊原 敬文, 相馬 友和, 秋山 泰利, 岩倉 芳倫, 塩飽 浩美, 鈴木 健弘, 阿部 倫明, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌　85　(1)　374-374　2009/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  88. 腎遠位尿細管イオンチャネルの機能局在を制御する分子機構

    種本 雅之, 豊原 敬文, 塩飽 浩美, 島 久登, 岩倉 芳倫, 相馬 友和, 秋山 泰利, 鈴木 健弘, 阿部 倫明, 阿部 高明, 伊藤 貞嘉

    日本腎臓学会誌　51　(3)　298-298　2009/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  89. 妊娠高血圧症候群8症例における血中エンドグリン濃度と血中ADMA濃度の検討

    秋山 泰利, 岩倉 芳倫, 相馬 友和, 豊原 敬文, 鈴木 健弘, 阿部 倫明, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本腎臓学会誌　51　(3)　307-307　2009/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  90. フルバスタチンはオレイン酸結合アルブミン刺激に伴う尿細管酸化ストレスを抑制する

    相馬 友和, 阿部 倫明, 秋山 泰利, 豊原 敬文, 鈴木 健弘, 塩飽 博美, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本腎臓学会誌　51　(3)　339-339　2009/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  91. 腎遠位尿細管管腔側カリウムチャネルの機能的発現機構の解明

    島 久登, 種本 雅之, 相馬 友和, 秋山 泰利, 岩倉 芳倫, 塩飽 浩美, 豊原 敬文, 鈴木 健弘, 阿部 倫明, 阿部 高明, 伊藤 貞嘉

    日本腎臓学会誌　51　(3)　350-350　2009/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  92. LOW LUMINAL pH AGGRAVATES FATTY ACID BOUD ALBUMIN INDUCED O-2(center dot-) PRODUCTION IN RENAL PROXIMAL TUBULAR CELL

    Tomokazu Souma, Michiaki Abe, Yasutoshi Akiyama, Takafumi Toyohara, Hiromi O. Shiwaku, Takehiro Suzuki, Masayuki Tanemoto, Takaaki Abe, Sadayoshi Ito

    JOURNAL OF PHYSIOLOGICAL SCIENCES　59　485-485　2009

    ISSN： 1880-6546

  93. 高グルコースによるアンギオテンシンII刺激後NAD(P)Hオキシダーゼ活性化の増強調節機序について

    阿部 倫明, 宮澤 紀子, 豊原 敬史, 相馬 友和, 秋山 泰利, 鈴木 健弘, 塩飽 浩美, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　31回　169-169　2008/10

    Publisher: (NPO)日本高血圧学会

  94. プラバスタチンは有機アニオントランスポーターを介して膵β細胞からのインスリン分泌を刺激する

    鈴木 健弘, 阿部 倫明, 豊原 敬文, 石井 晶子, 野口 直哉, 秋山 泰利, 相馬 友和, 塩飽 浩美, 種本 雅之, 伊藤 貞嘉, 阿部 高明

    日本高血圧学会総会プログラム・抄録集　31回　190-190　2008/10

    Publisher: (NPO)日本高血圧学会

  95. 妊娠高血圧症候群8症例における血中エンドグリン濃度の検討

    秋山 泰利, 相馬 友和, 豊原 敬文, 鈴木 健弘, 阿部 倫明, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　31回　360-360　2008/10

    Publisher: (NPO)日本高血圧学会

  96. 褐色細胞腫および傍神経節腫の診断における随時尿メタネフリン分画・クレアチニン比の有用性について

    相馬 友和, 秋山 泰利, 豊原 敬文, 鈴木 健弘, 阿部 倫明, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　31回　365-365　2008/10

    Publisher: (NPO)日本高血圧学会

  97. 生理的レベルの副腎皮質刺激が副腎静脈サンプリングの診断に及ぼす影響

    種本 雅之, 秋山 泰利, 相馬 友和, 鈴木 健弘, 阿部 倫明, 阿部 高明, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集　31回　367-367　2008/10

    Publisher: (NPO)日本高血圧学会

  98. 【CKD 早期介入の意義と期待効果】病因・病態 病態からみた心-腎連関

    秋山 泰利, 伊藤 貞嘉

    日本臨床　66　(9)　1701-1705　2008/09

    Publisher: (株)日本臨床社

    ISSN： 0047-1852

  99. メサンギウム細胞における高グルコース曝露がアンジオテンシンII刺激による酸化ストレス産生を増強させる機序について

    阿部 倫明, 宮澤 紀子, 豊原 敬文, 相馬 友和, 鈴木 健弘, 秋山 泰利, 塩飽 浩美, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌　84　(2)　693-693　2008/09

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  100. 腎動脈起始部の腫瘤性病変により腎血管性高血圧を呈したと考えられる一例

    大平 未佳, 秋山 泰利, 阿部 倫明, 阿部 高明

    日本心臓病学会誌　2　(Suppl.I)　194-194　2008/08

    Publisher: (一社)日本心臓病学会

    ISSN： 1882-4501

  101. 褐色細胞腫および傍神経節腫への非イオン性ヨード造影剤使用に伴う合併症の検討

    相馬 友和, 秋山 泰利, 豊原 敬文, 鈴木 健弘, 阿部 倫明, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌　84　(1)　252-252　2008/04

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  102. 腎動脈狭窄症の狭窄部圧格差と血行再建術の治療効果の関連

    種本 雅之, 秋山 泰利, 相馬 友和, 阿部 倫明, 阿部 高明, 伊藤 貞嘉

    日本腎臓学会誌　50　(3)　284-284　2008/04

    Publisher: (一社)日本腎臓学会

    ISSN： 0385-2385

    eISSN： 1884-0728

  103. トランスポーター研究の新展開 医療現場におけるトランスポーター研究の応用

    阿部 高明, 豊原 敬文, 秋山 泰利, 阿部 倫明, 鈴木 健弘, 種本 雅之, 野口 直哉, 高沢 伸

    薬剤学: 生命とくすり　68　(Suppl.)　24-24　2008/04

    Publisher: (公社)日本薬剤学会

    ISSN： 0372-7629

    eISSN： 2188-3149

  104. RAS阻害およびPTRAにてネフローゼ域蛋白尿からの著明な改善を得た腎血管性高血圧の一例

    相馬友和, 閻国珊, 秋山泰利, 豊原敬文, 鈴木健弘, 阿部倫明, 種本雅之, 阿部高明, 伊藤貞嘉

    日本腎臓学会誌　50　(6)　2008

    ISSN： 0385-2385

  105. アンジオテンシンIIとブドウ糖は異なる様式でメサンギウム細胞の酸化ストレスを産生させた

    阿部 倫明, 宮澤 紀子, 豊原 敬文, 中山 謙二, 鈴木 健弘, 秋山 泰利, 塩飽 浩美, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌　83　(2)　589-589　2007/09

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  106. Pravastatinは有機アニオントランスポーターを介して膵β細胞からのインスリン分泌を刺激する

    阿部 倫明, 豊原 敬文, 鈴木 健弘, 秋山 泰利, 種本 雅之, 伊藤 貞嘉, 阿部 高明

    日本内分泌学会雑誌　83　(2)　593-593　2007/09

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  107. 近位尿細管特異的GFP-tTA発現マウスの作製と解析

    豊原 敬文, 鈴木 健弘, 阿部 倫明, 秋山 泰利, 種本 雅之, 伊藤 貞嘉, 阿部 高明

    日本内分泌学会雑誌　83　(2)　595-595　2007/09

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  108. 経皮経管腎動脈拡張術後の再狭窄がロサルタン内服後の正常血圧の維持により改善した一例

    秋山 泰利, 種本 雅之, 豊原 敬文, 鈴木 健弘, 阿部 倫明, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌　83　(2)　598-598　2007/09

    Publisher: (一社)日本内分泌学会

    ISSN： 0029-0661

    eISSN： 2186-506X

  109. 当院における関節リウマチに対するTNF-α阻害薬の使用経験

    秋山 泰利, 浅村 孝昭, 鵜生川 久美, 道下 吉広, 牧 伸樹, 黒木 淳, 西成 民夫, 朝倉 健一, 西村 茂樹

    秋田県農村医学会雑誌　53　(1)　71-71　2007/07

    Publisher: (一財)秋田県農村医学会

    ISSN： 0002-368X

  110. 高齢者のPh陽性ALLにイマチニブ治療を併用した一例

    浅村 孝昭, 黒木 淳, 西成 民夫, 道下 吉宏, 牧 伸樹, 秋山 泰利, 藤原 崇史, 工藤 大輔, 朝倉 健一, 西村 茂樹

    秋田県農村医学会雑誌　52　(2)　50-50　2007/02

    Publisher: (一財)秋田県農村医学会

    ISSN： 0002-368X

  111. DEVELOPMENT OF THE RENAL PROXIMAL TUBULE SPECIFIC-INDUCIBLE GENE EXPRESSION SYSTEM

    Takafumi Toyohara, Takehiro Suzuki, Michiaki Abe, Yasutoshi Akiyama, Hiromi Shiwaku, Eisuke Shibata, Masayuki Tanemoto, Sadayoshi Ito, Takaaki Abe

    DRUG METABOLISM REVIEWS　39　331-331　2007

    ISSN： 0360-2532

  112. 成人発症でprecursor NK細胞性と考えられるALLの一例

    西成 民夫, 黒木 淳, 北原 栄, 斉藤 邦江, 牧 伸樹, 秋山 泰利, 浅村 孝昭, 篠原 良徳, 五十嵐 巌, 新妻 展近, 朝倉 健一, 西村 茂樹, 杉田 暁大

    秋田県農村医学会雑誌　51　(2)　49-49　2006/02

    Publisher: (一財)秋田県農村医学会

    ISSN： 0002-368X

  113. 薬物治療抵抗性関節リウマチ(RA)に対する白血球除去療法の経験

    秋山 泰利, 工藤 宏仁, 中村 崇宣, 須田 秀司, 西村 茂樹, 熊谷 芳樹, 北島 正一, 市村 靖

    秋田県農村医学会雑誌　51　(1)　40-40　2005/07

    Publisher: (一財)秋田県農村医学会

    ISSN： 0002-368X

Show all ︎Show first 5

Research Projects 4

  1. ミトコンドリアtRNA修飾核酸の網羅的測定による新規ミトコンドリア病診断法の確立

    秋山 泰利, 豊原 敬文

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2021/04/01 - 2024/03/31

    More details Close

    本研究は、(1)ミトコンドリアからのtRNAsの効率的な抽出、(2) ミトコンドリア病患者から樹立したヘテロプラスミーの異なるiPS細胞クローンからの心筋誘導、(3) LC-MS/MSによる修飾核酸の一斉定量、の3項目を大きな柱としている。ミトコンドリアtRNAsの抽出に関しては最適化を進め、まず培養細胞のtotal RNAを用いてtRNAs特異的なプルダウンによるtRNAs抽出法の確立を行なった。さらにミトコンドリアRNAの簡易かつ効率的な精製の条件検討を行ない、前述のtRNAs抽出法がミトコンドリアtRNAsに対しても同様に効率よく行えることを確認した。iPS細胞からの心筋への誘導はクローンごとの誘導効率の差異が認められることから、クローン間の誘導効率の均一性を上昇させるためにさらなる検討を進めている。LC-MS/MSの測定系では、一斉定量可能な修飾核酸種の拡充を進めており、τm5s2U, ms2i6A, τm5U, f5Cといったミトコンドリア特異的な修飾核酸も測定系に加えることができた。実際ミトコンドリアRNAを培養細胞から抽出し、サンプル調整を行い測定を行うことで、これらの修飾核酸の検出および定量に成功した。 申請者の考案したtRNAsの濃縮法は、tRNAsの高次構造（tRNAの3'-CCA末端）特異的に結合するDNAオリゴと成熟tRNAsを連結させるものである。本研究の予備検討としてこの手法の最適化を行い、さらにこの手法を用いて、tRNAsの3'-CCA末端が細胞のストレスにより切断されることを明らかにした。以上の結果は本研究の重要な基礎データとなるものであり論文として報告を行なった。

  2. Search for molecules that control the CD39-CD73-adenosine cascade and expand into drug discovery

    Tomioka Yoshihisa

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2019/04/01 - 2022/03/31

    More details Close

    Enzymatic evaluation methods and enzymatic evaluation methods for compounds that inhibit or increase the enzymatic activity of CD73 or CD39 for the small molecule discovery of novel cancer immunotherapy targeting the PD-1 / PD-L1 independent immunosuppressive pathway. As a result of screening and evaluating 6,080 species of the Tohoku University compound library using the evaluation method using mouse spleen cells, 19 promising seed candidate compounds were obtained. We succeeded in obtaining three compounds selective for CD73 from the enzyme reaction curves of one of the 13 analog compounds.

  3. Kidney transporter and gut microbiota as therapeutic targets for chronic kidney disease

    Akiyama Yasutoshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2014/04/01 - 2017/03/31

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    (1) We comprehensively evaluated serum concentrations of 122 ionic compounds in hemodialysis (HD) patients. We identified 38 solutes and 23 solutes that were higher and lower, respectively, in HD patients than non-dialyzed chronic kidney disease (CKD) patients. (2) We revealed that a newly synthesized indole derivative (MA-5) increased cellular ATP level and survival of fibroblasts from patients with mitochondrial diseases. These data suggest that MA-5 has the potential to become a novel therapeutic drug for treatment of mitochondrial diseases. (3) We revealed that ClC-2 chloride channel activator lubiprostone improved the gut microbiota, resulting in amelioration of CKD progression. (4) Using next-generation sequencing, we examined whether ribonuclease angiogenin (ANG) cleaves CCA-termini of tRNAs in vivo. The proportion of tRNA-derived fragments with CCA did not increase in ANG-treated cells, suggesting that ANG does not cleave CCA-termini in vivo.

  4. Regulation of SLCO4C1 transporter-mediated excretion of uremic toxins as a therapeutic strategy for Chronic Kidney Disease

    AKIYAMA Yasutoshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Research Activity Start-up

    Institution: Tohoku University

    2012/08/31 - 2014/03/31

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    Chronic kidney disease (CKD) is a global health problem that carries a substantial risk for cardiovascular morbidity and death. With the progression of CKD, various uremic toxins accumulate, subsequently causing renal damage and hypertension. Recently, we have revealed that kidney-specific organic anion transporter SLCO4C1 excretes uremic toxins, and the up-regulation of SLCO4C1 resulted in the reduction of blood pressure and renal inflammation in a CKD model. In this study, we revealed that indoxyl sulfate (IS), one of the best-known uremic toxins, inhibits the expression of SLCO4C1 through GATA3 and that removal of IS increases the SLCO4C1 expression. The combination therapy of, (1) activating the SLCO4C1 expression by statins, (2) reducing the plasma IS concentration by the administration of AST-120 and (3) administering GATA inhibitor, could be a more effective remedy for the excretion of uremic toxins and preservation of renal function in CKD patients.