Search for uremia suppressive therapeutics based on investigation on role of sulfate-conjugated uremic solutes in development and pregoression of kidney injury

• Project/Area Number: 17H04104
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kumamoto University
• Principal Investigator: SAITO HIDEYUKI 熊本大学, 病院, 教授 (40225727)
• Co-Investigator(Kenkyū-buntansha): 城野 博史 熊本大学, 病院, 准教授 (40515483)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 尿毒症物質 / 急性腎障害 / 硫酸転移酵素 / シスプラチン腎症 / 活性酸素種 / 治療薬開発 / 腎障害 / 慢性腎臓病

Outline of Final Research Achievements

Acute kidney injury (AKI) induced by cisplatin recognized as a severe side effect in clinical, because the occurrence of AKI lead to decrease in dosage and discontinuation of cisplatin treatment. It is known that various factors such as oxidative stress, apoptosis, and DNA damage are involved in the molecular mechanisms of cisplatin-induced AKI. However, the factor accelerate the progression and deterioration of cisplatin-induced AKI remain undetermined. We previously reported that in cisplatin-induced AKI rat, inhibition of indooxyl sulfate (IS), a typical sulfate-conjugated uremix toxin, presented nephroprotective effect. In order to reveal toxico-pathological role of IS more clearly, we used sult1a1 deficient mice in which IS production was inhibited, and HK-2 cells treated with IS and cisplatin. This study revealed that IS in cisplatin-induced AKI by increased reactive oxygen species production via aryl hydrocarbon receptor (AhR), and downregulated antioxidant enzymes.

Academic Significance and Societal Importance of the Research Achievements

本研究課題では、インドキシル硫酸がシスプラチン誘発急性腎障害において活性酸素種の産生を亢進することにより腎組織及び機能障害を惹起することが明らかとなり、インドキシル硫酸が腎臓の病態形成において重要な役割を果たす毒性因子であることを突き止めた。臨床で使用されている吸着活性炭 AST-120 は服用量が多く服薬アドヒアランスの低い薬剤であるため、IS の産生を抑制する新規機序の治療薬が必要とされている。硫酸転移酵素Sult1a1の欠損マウスを用いた動物試験により、インドキシル硫酸の産生抑制とともに腎障害軽減効果が観察されたことから、Sult1a1 が新規治療薬の標的となる可能性が示唆された。

Research Products

• [Journal Article] A novel step‐down infusion method of barbiturate therapy: Its safety and effectiveness for intracranial pressure control (2021)
  • Author(s): Yamakawa Yukako、Morioka Motohiro、Negoto Tetsuya、Orito Kimihiko、Yoshitomi Munetake、Nakamura Yukihiko、Takeshige Nobuyuki、Yamamoto Masafumi、Takeuchi Yasuharu、Oda Kazutaka、Jono Hirofumi、Saito Hideyuki
  • Journal Title: Pharmacology Research & Perspectives Volume: 9 Issue: 2
  • DOI: 10.1002/prp2.719
  • Peer Reviewed / Open Access
• [Journal Article] Suppressed Hepatic Production of Indoxyl Sulfate Attenuates Cisplatin-Induced Acute Kidney Injury in Sulfotransferase 1a1-Deficient Mice (2021)
  • Author(s): Yabuuchi Nozomi、Hou Huixian、Gunda Nao、Narita Yuki、Jono Hirofumi、Saito Hideyuki
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 4 Pages: 1764-1764
  • DOI: 10.3390/ijms22041764
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between clinicopathological characteristics and CYLD expression in patients with cholesteatoma (2020)
  • Author(s): Miyake Shunsuke、Miwa Toru、Yoneda Go、Kanemaru Ayumi、Saito Haruki、Minoda Ryosei、Orita Yorihisa、Saito Hideyuki、Jono Hirofumi
  • Journal Title: PLOS ONE Volume: 15 Issue: 10 Pages: e0240216-e0240216
  • DOI: 10.1371/journal.pone.0240216
  • Peer Reviewed / Open Access
• [Journal Article] Ribosomal protein S6 promotes stem‐like characters in glioma cells (2020)
  • Author(s): Shirakawa Yuki、Hide Takuichiro、Yamaoka Michiko、Ito Yuki、Ito Naofumi、Ohta Kunimasa、Shinojima Naoki、Mukasa Akitake、Saito Hideyuki、Jono Hirofumi
  • Journal Title: Cancer Science Volume: 111 Issue: 6 Pages: 2041-2051
  • DOI: 10.1111/cas.14399
  • Peer Reviewed / Open Access
• [Journal Article] Comparative Study of Constipation Exacerbation by Potassium Binders Using a Loperamide-Induced Constipation Model (2020)
  • Author(s): Narita Yuki、Fukumoto Koichi、Fukunaga Masaki、Kondo Yuki、Ishitsuka Yoichi、Jono Hirofumi、Irie Tetsumi、Saito Hideyuki、Kadowaki Daisuke、Hirata Sumio
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 7 Pages: 2491-2491
  • DOI: 10.3390/ijms21072491
  • Peer Reviewed / Open Access
• [Journal Article] Development and evaluation of a vancomycin dosing nomogram to achieve the target area under the concentration-time curve. A retrospective study. (2019)
  • Author(s): Oda K, Katanoda T, Hashiguchi Y, Kondo S, Narita Y, Iwamura K, Nosaka K, Jono H, Saito H
  • Journal Title: J Infect Chemother. Volume: 26 Pages: 444-450
  • Peer Reviewed / Open Access
• [Journal Article] Loss of tumor suppressor CYLD expression triggers cisplatin resistance in oral squamous cell carcinoma. (2019)
  • Author(s): Suenaga N, Kuramitsu M, Komure K, Kanemaru A, Takano K, Ozeki K, Nishimura Y, Yoshida R, Nakayama H, Shinriki S, Saito H, Jono H.
  • Journal Title: J Mol Sci Volume: 20 Issue: 20 Pages: 5194-5194
  • DOI: 10.3390/ijms20205194
  • Peer Reviewed / Open Access
• [Journal Article] Edoxaban Exerts Antioxidant Effects Through FXa Inhibition and Direct Radical-Scavenging Activity. (2019)
  • Author(s): Narita Y, Hamamura K, Kashiyama M, Utsumi S, Kakizoe Y, Kondo Y, Ishitsuka Y, Jono H, Irie T, Mukoyama M, Saito H, Kadowaki D, Hirata S, Kitamura K.
  • Journal Title: Int J Mol Sci. Volume: 20
  • Peer Reviewed / Open Access
• [Journal Article] Continuous high-dose infusion of doripenem in a pneumonia patient infected by carbapenem-resistant Pseudomonas aeruginosa: a case report (2019)
  • Author(s): Oda K, Kamohara H, Katanoda T, Hashiguchi Y, Iwamura K, Nosaka K, Jono H, Saito H.
  • Journal Title: J Pharm Health Care Sci. Volume: 5 Pages: 1-1
  • Peer Reviewed / Open Access
• [Journal Article] Doxycycline attenuates cisplatin-induced acute kidney injury through pleiotropic effects. (2018)
  • Author(s): Nakagawa T, Kakizoe Y, Iwata Y, Miyasato Y, Mizumoto T, Adachi M, Izumi Y, Kuwabara T, Suenaga N, Narita Y, Jono H, Saito H, Kitamura K, Mukoyama M.
  • Journal Title: Am J Physiol Renal Physiol. Volume: 315
  • Peer Reviewed / Open Access
• [Journal Article] Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters (2018)
  • Author(s): Endo-Tsukude C, Sasaki JI, Saeki S, Iwamoto N, Inaba M, Ushijima S, Kishi H, Fujii S, Semba H, Kashiwabara K, Tsubata Y, Hayashi M, Kai Y, Saito H, Isobe T, Kohrogi H, Hamada A.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 1 Pages: 47-56
  • DOI: 10.1248/bpb.b17-00521
  • NAID: 130006301216
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency. (2017)
  • Author(s): Aoki M, Hayashi H, Rao KV, Das D, Higashi-Kuwata N, Bulut H, Aoki-Ogata H, Takamatsu Y, Yedidi RS, Davis DA, Hattori SI, Nishida N, Hasegawa K, Takamune N, Nyalapatla PR, Osswald HL, Jono H, Saito H, Yarchoan R, Misumi S, Ghosh AK, Mitsuya H.
  • Journal Title: Elife Volume: 6
  • DOI: 10.7554/elife.28020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] UNILATERAL URETER OBSTRUCTION (UUO)-INDUCED RENAL FIBROSIS IS ATTENUATED BY SUPPRESSION OF INDOXYL SULFATE (IS) ACCUMULATION IN SULFOTRANSFERASE (SULT)1A1-DEFICIENT MICE (2020)
  • Author(s): Huixian Hou, Nozomi Yabuuchi, Nao Gunda, Rika Fujino, Yuya Hayashi, Yuki Narita, Hirofumi Jono, Hideyuki Saito
  • Organizer: ・The 57th European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Fully Virtual Congress
  • Int'l Joint Research
• [Presentation] 硫酸抱合型尿毒素の産生責任酵素SULT1A1を標的とした腎障害進展抑制治療薬の探索 (2020)
  • Author(s): 齋藤秀之
  • Organizer: 第30回日本医療薬学会年会
• [Presentation] 糖尿病（DM）併発虚血性急性腎障害（AKI）ラットの病態進展におけるインドキシル硫酸（IS）の関与 (2019)
  • Author(s): 鵜木隼平、小山直子、下河優奈、城野博史、齋藤秀之
  • Organizer: 第62回日本腎臓学会学術総会
• [Presentation] 血液透析患者における心血管合併症および予後予測因子としてのインドキシル硫酸の有用性検証 (2019)
  • Author(s): 松下馨介、米田剛、中田悦史、西一彦、城野博史、齋藤秀之
  • Organizer: 第62回日本腎臓学会学術総会
• [Presentation] Ischemia-Reperfusion-Induced AKI (IR-AKI) Associated with Renal Fibrosis Is Attenuated Through Suppressing Indoxyl Sulfate Accumulation in Sulfotransferase (Sult) 1a1-Deficient Mice (2019)
  • Author(s): Matsushita K, Gunda N, Fujino R, Nishigaki A, Hayashi Y, Nishi K, Jono H, Saito H
  • Organizer: Kidney Week 2019, American Society of Nephrology Annual Meeting
  • Int'l Joint Research
• [Presentation] Unilateral Ureter Obstruction (UUO)-Induced Renal Fibrosis Is Attenuated by Suppression of Indoxyl Sulfate (IS) Accumulation in Sulfotransferase (Sult)1a1-Deficient Mice (2019)
  • Author(s): Huixian H, Fujino R, Hayashi Y, Unoki J, Matsushita K, Gunda N, Jono H, Saito H
  • Organizer: Kidney Week 2019, American Society of Nephrology Annual Meeting
• [Presentation] Sulfotransferase (Sult) 1a1 plays a toxico- pathological role in cisplatin-induced acute kidney injury (AKI) through metabolic generation of indoxyl sulfate (IS) (2019)
  • Author(s): Hou K, Fujino R, Unoki S; Tanaka H; Matsushita K, Gunda N, Jono H, Saito H
  • Organizer: World Congress of Nephrology 2019
  • Int'l Joint Research
• [Presentation] 低酸素条件下におけるインドキシル硫酸の腎線維化亢進作用メカニズムの解明 (2017)
  • Author(s): 山下真美、衛藤萌、米田剛、藤野梨香、城野博史、齋藤秀之
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] 分子病理学的解析に基づいたアデニン誘発性慢性腎臓病モデル動物の有用性検証 (2017)
  • Author(s): 飯田優美、阿部絵理佳、藤野梨香、城野博史、齋藤秀之
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] Elucidation of mechanism for indoxyl sulfate (IS)-promoted renal fibrotic response in HK-2 cells under hypoxic condition and mice with ischemia-reperfusion (IR)-induced AKI (2017)
  • Author(s): Yamashita M, Eto M, Yoneda G, Fujino R, Jono H, Saito H
  • Organizer: ・Kidney Week 2017, American Society of Nephrology Annual Meeting
  • Int'l Joint Research
• [Presentation] Experimental confirmation of toxico-pharmacological role of sulfate-conjugated uremic solutes in cisplatin nephropathy (2017)
  • Author(s): Fujino R, Unoki S, Tanaka H, Matsushita K, Yoneda G, Miyake S, Jono H, Saito H
  • Organizer: ・Kidney Week 2017, American Society of Nephrology Annual Meeting
  • Int'l Joint Research
• [Book] Uremic Toxins and Organ Failure (2020)
  • Author(s): Hideyuki Saito, Takaaki Abe
  • Total Pages: 180
  • Publisher: Springer Nature
• [Book] 腎と透析増刊号・腎と透析ベッドサイド検査事典 (2018)
  • Author(s): 齋藤秀之
  • Total Pages: 471
  • Publisher: 東京医学社