The small GTPase Rho and its effector Rho-kinase are involved in the pathogenesis of diabetic kidney disease. Accumulating evidence shows that renal dysfunction in diabetic patient is associated with abnormal fatty acid oxidation in the kidney. However, the interaction of Rho-kinase and fatty acid oxidation in diabetic kidney remain unclear. Glomeruli isolated from type 2 diabetic db/db mice demonstrated decreased gene expression of fatty acid oxidation mediators such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), CD36, carnitine palmitoyltransferase 1A (CPT1A). Chemical inhibition of Rho-kinase restored expression of fatty acid oxidation-related genes in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated Rho-kinase functions through the phosphorylation of AMPK and increased expression of PGC-1α. Extracellular flux analyzer demonstrated that Rho-kinase inhibition improves TGF-β-induced mitochondrial dysfunction. Furthermore, fluorescence histochemistry showed that Rho-kinase inhibitors suppresses ROS production as a result of mitochondrial damage due to abnormal fatty acid metabolism. Knockdown by small interfering RNA against two Rho-kinase isoforms, ROCK1 and ROCK2, showed that ROCK1 but not ROCK2 controls this metabolic machinery. Consistent with this result, mesangial cells isolated from ROCK1 deficient mice were protected from TGF-β-mediated downregulation of fatty acid metabolism. These observations indicate that ROCK1 is a key player in the development of diabetic renal injury. Glomerular ROCK1 may be a potential therapeutic target for the treatment of diabetic kidney disease.
Y. Nagai: None. K. Matoba: Research Support; Self; Sanofi K.K., Takeda Pharmaceutical Company Limited. Y. Takeda: None. T. Akamine: None. D. Kawanami: None. K. Utsunomiya: None. R. Nishimura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K.K., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi K.K., Takeda Pharmaceutical Company Limited.