2020 Fiscal Year Final Research Report
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
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Kumamoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
城野 博史 熊本大学, 病院, 准教授 (40515483)
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| 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 |
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| 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.
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| Free Research Field |
腎臓生理学・毒性学
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| 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。
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