ROCK2-induced metabolic rewiring in diabetic kidney disease

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08645
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Matoba Keiichiro 東京慈恵会医科大学, 医学部, 准教授 (20459647)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 糖尿病 / 糖尿病腎症 / 糖尿病性腎症 / 慢性腎臓病 / 糸球体上皮細胞 / ROCK / ROCK2 / PPARα

Outline of Final Research Achievements

Podocyte loss is a common feature of diabetic nephropathy. We described that podocyte Rho associated coiled-coil containing protein kinase 2 (ROCK2) is activated in rodent models and patients with diabetes. Podocyte-specific ROCK2 deletion mice were resistant to albuminuria, glomerular fibrosis, and podocyte loss in multiple animal models of diabetes. RNA-sequencing of ROCK2-ablated podocytes provided evidence indicating ROCK2 as a critical regulator of cellular metabolism. In particular, ROCK2 serves as a suppressor of peroxisome proliferator-activated receptors α (PPARα), which negatively regulate the transcription of genes involved in fatty acid oxidation and consequently induce podocyte death. Our data suggest ROCK2 as an essential regulator of podocyte energy homeostasis.

Free Research Field

糖尿病学

Academic Significance and Societal Importance of the Research Achievements

糖尿病腎症は糖尿病患者の生命予後を規定する血管併発症であり、生活の質を維持するためにも病態の進行抑制が求められる。本研究から、ROCK2が腎エネルギー代謝と腎症の進行を制御する重要なシグナル分子であることが明らかになり、ROCK2を標的とした創薬と腎症に対する新たな治療戦略確立へ向けた大きな第一歩となった。ROCK2は糖尿病腎症のみならず、悪性腫瘍や中枢神経疾患など、広範な疾病の病態に関与しており、本研究をさらに発展させることで、「細胞内シグナル伝達異常」という観点から様々な疾患の病因解明、診断、創薬に向けたシーズ探索が可能となる。