2022 Fiscal Year Final Research Report
Study on the mechanisms of kidney disease progression and their regulation: roles of chronic inflammation and humoral mediators
Project/Area Number |
20K08611
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53040:Nephrology-related
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Research Institution | Kumamoto University |
Principal Investigator |
MUKOYAMA Masashi 熊本大学, 大学院生命科学研究部(医), 教授 (40270558)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Keywords | 慢性腎臓病 / 慢性炎症 / 糖尿病性腎症 / マクロファージ / ERストレス / MRP8 / ANGPTL2 / オステオクリン |
Outline of Final Research Achievements |
Chronic kidney disease (CKD) is a growing health problem worldwide. The mechanisms for CKD progression remain obscure, and therefore we explored key factors, focusing on chronic inflammation and humoral factors. We found that a macrophage-derived factor MRP8 is critical in disease progression through intra-glomerular crosstalk, activated by mesangium-derived exosomes. Mesangium-derived factors also impair podocyte function in diabetes through inhibition of ER-associated degradation. We found several factors that may aggravate CKD with diabetes by single-cell RNA analysis. A potential proinflammatory factor ANGPTL2, in contrast, may work renoprotective in an ischemia-reperfusion injury (IRI) model. In addition, bone-derived osteocrin can exert renoprotective actions upon IRI by potentiating natriuretic peptide actions locally. Furthermore, high serum levels of MRP8 and ANGPTL2 can be risk factors in hemodialysis patients. These findings may provide potential therapeutic targets for CKD.
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Free Research Field |
内科系臨床医学・腎臓内科学
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Academic Significance and Societal Importance of the Research Achievements |
糖尿病性腎症に代表されるmetabolic kidney diseaseにおける局所因子の意義、特にマクロファージ由来炎症惹起因子の増悪因子としての役割を明らかにすることで、これらを標的とした新たな創薬への基盤となる。さらに、急性腎障害慢性化の機序を明らかにすることで腎症進展阻止のための治療戦略となりうる。MRP8やANGPLT2、オステオクリンはその候補分子であり、これらを標的とした治療法はなく、病態での意義の解析から新たな治療戦略の提案へと繋がる可能性がある。一方で、これらの血中濃度は腎症患者の予後予測におけるバイオマーカーとしての意義が示唆され、今後の腎疾患診療に貢献する可能性が高い。
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