| Project/Area Number |
15H04837
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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 |
Kidney internal medicine
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| Research Institution | Teikyo University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
藤田 敏郎 東京大学, 先端科学技術研究センター, 名誉教授 (10114125)
内田 俊也 帝京大学, 医学部, 教授 (50151882)
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| Research Collaborator |
Lifton Richard P
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2015: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
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| Keywords | リン酸化 / ユビキチン・プロテアソーム系 / 慢性腎臓病 / 高血圧 / 膜輸送体 / 核内受容体 / 電解質異常 / 翻訳後修飾 / ユビキチンリガーゼ / 体液恒常性 / ミネラロコルチコイド受容体 / 電解質調節 |
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| Outline of Final Research Achievements |
Global responses of the kidney to physiological perturbations can be determined by the coordinate action of different constituent kidney cells. In this study, we evaluated signaling pathways involved in the cell-selective control of renal tubular cells, especially focusing on mineralocorticoid receptor, a steroid receptor, and the ubiquitin ligase component Kelch-like 3. We found that mineralocorticoid receptor in intercalated cells are selectively controlled by phosphorylation, which is regulated by angiotensin II signaling through mTOR-ULK1 pathway. We also found that Kelch-like 3 acts downstream of angiotensin II and plasma K alterations, regulating NaCl cotransporter in distal convoluted tubule cells. These effects are integrated to produce appropriate kidney responses in response to the activation of renin-angiotensin-aldosterone system, and the dysregulation of these mechanisms can be involved in fluid and electrolyte abnormalities associated with diverse kidney diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
慢性腎臓病は本邦の国民病ともいわれており、腎臓病の予後改善に向けて病態基盤の解明と理解が不可欠である。高血圧は慢性腎臓病の主要な進展因子であり、中でもレニン・アンジオテンシン・アルドステロン系の病的な活性化は高血圧の発症と腎臓病の進展の両者に深く関与している。本研究より、腎臓内での翻訳後修飾を介したシグナル伝達機構の詳細と、腎臓病における病的役割が解明されつつある。特にアンジオテンシンIIが様々な尿細管細胞に作用する分子基盤の詳細や、野菜や果物などカリウムを多く含む食物(DASH食)の降圧作用・臓器保護作用の一端が明らかとなってきており、腎・高血圧疾患の診療に有用な情報が蓄積されている。
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