1384-P: Distinct Role of ROCK1 in the Regulation of Fatty Acid Energy Metabolism in Kidney Tubules

Introduction and Objective: In diabetic kidney disease, tubular injury is closely linked to impaired fatty acid oxidation, resulting in mitochondrial dysfunction and reduced ATP generation, which in turn drives inflammatory and fibrotic responses. Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine/threonine kinase downstream of Rho. Two isoforms, ROCK1 and ROCK2, are widely expressed in the kidney. Although both isoforms affect energy metabolism in glomeruli, their isoform-specific roles in kidney tubular metabolism remain poorly defined. This study aimed to elucidate the distinct roles of ROCK isoforms in regulating fatty acid metabolism in kidney tubules. Methods: Human proximal tubular cells (HK-2) were stimulated with transforming growth factor-β (TGF-β). ROCK signaling was inhibited using a pharmacological ROCK inhibitor or siRNA targeting ROCK1 or ROCK2. In addition, the kidney phenotype of tubular-specific ROCK1 knockout mice (TR1KO) was evaluated. Results: In HK-2 cells, TGF-β markedly suppressed the expression of peroxisome proliferator-activated receptor-α (PPARα) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), accompanied by a reduction in ATP production. A ROCK inhibitor significantly reversed the TGF-β-induced downregulation of PPARα and PGC-1α, and restored intracellular ATP levels. Selective knockdown of ROCK1 prevented the TGF-β-induced suppression of PPARα and PGC-1α, whereas knockdown of ROCK2 had no appreciable effect. In a high-fat diet model, TR1KO mice showed no significant differences in body weight or serum lipid profiles compared with wild-type mice; however, kidney expression of PPARα and PGC-1α was significantly upregulated. Conclusion: Fatty acid energy metabolism in kidney tubules is negatively regulated by ROCK1, predominantly through the suppression of PPARα- and PGC-1α-mediated metabolic pathways. Disclosure S. Nagao: None. K. Matoba: None. S. Ohashi: Research Support; Ended; Novo Nordisk. Y. Nagai: None. N. Rimei: Advisory Panel; Current; Abbott Japan Co., Ltd. Speaker's Bureau; Current; ARKRAY USA, Inc., Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Eli Lilly and Company, Sanofi K.K., Medtronic, Taisho Pharmaceutical Holdings Co., Ltd.