392-P: ROCK2-Mediated Podocyte Dysfunction in Diabetic Nephropathy

The small GTPase RhoA and its downstream effector, Rho-kinase (ROCK), are implicated in a variety of cellular functions (e.g., cell adhesion, migration) via effect on cytoskeletal reorganization. We and others have illuminated ROCK as an important pathogenic regulator of diabetic kidney disease. Renal ROCK activity is elevated in both type 1 and type 2 diabetic murine models, as well as in diabetic patients. ROCK has two isoforms, ROCK1 and ROCK2. ROCK1 has been shown to regulate mitochondrial fission and epithelial-to-mesenchymal transition in the setting of diabetic kidney disease: however, the role of renal ROCK2 remain unclear. In the present study, we have demonstrated the upregulation of ROCK2 in glomerular podocytes obtained from 3 established models of diabetic kidney disease, (i.e., streptozotocin injection, db/db, and high-fat diet treatment), and diabetic patients. In an attempt to elucidate the roles of podocyte ROCK2, we generated podocyte-specific ROCK2 knockout mice (PR2KO) by breeding ROCK2 flox mice with Podocin-Cre mice. We found that podocyte-restricted ROCK2 deletion did not lead to any defects in the kidney development and functions. Of note, PR2KO were protected against albuminuria and glomerular sclerosis in streptozotocin-induced diabetic mice. In addition, renoprotective actions of podocyte ROCK2 deletion were also observed in type 2 diabetic db/db mice and high-fat diet-fed animals. Mechanistically, RNA-Seq analysis in ROCK2-null podocytes revealed the recovery of fatty acid utilization. When considered alongside our previous observations, the current work highlights the importance of ROCK2 in diabetic podocytopathy. Disclosure K. Matoba: Research Support; Self; Eli Lilly Japan K. K. Y. Takeda: None. T. Akamine: None. Y. Nagai: None. R. Ukichi: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker’s Bureau; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Medtronic, MSD Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Japan Society for the Promotion of Science (20K08645, 18K15985); Suzuken Memorial Foundation; Takeda Science Foundation; Yokoyama Foundation for Clinical Pharmacology; MSD Life Science Foundation; Ichiro Kanehara Foundation; Japan Diabetes Foundation; Ueh