ROCK2-induced metabolic rewiring in diabetic podocytopathy

• Published in: Communications biology Vol. 5; no. 1; p. 341
• Main Authors: Matoba, Keiichiro, Takeda, Yusuke, Nagai, Yosuke, Sekiguchi, Kensuke, Ukichi, Rikako, Takahashi, Hiroshi, Aizawa, Daisuke, Ikegami, Masahiro, Tachibana, Toshiaki, Kawanami, Daiji, Kanazawa, Yasushi, Yokota, Tamotsu, Utsunomiya, Kazunori, Nishimura, Rimei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.04.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/51; 13/89; 14/28; 14/63; 38/91; 631/80/304; 692/4022/1585/2759/1419; Albuminuria - metabolism; Animal models; Animals; Apoptosis; Biology; Biomedical and Life Sciences; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Energy balance; Fatty acids; Fibrosis; High fat diet; Homeostasis; Humans; Kidneys; Kinases; Life Sciences; Metabolism; Mice; Oxidation; Patients; Peroxisome proliferator-activated receptors; Podocytes - metabolism; Protein kinase; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; Signal transduction; Streptozocin; Streptozocin - adverse effects; Streptozocin - metabolism; Transcription
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03300-4

Loss of podocytes is a common feature of diabetic renal injury and a key contributor to the development of albuminuria. We found that podocyte Rho associated coiled-coil containing protein kinase 2 (ROCK2) is activated in rodent models and patients with diabetes. Mice that lacked ROCK2 only in podocytes (PR2KO) were resistant to albuminuria, glomerular fibrosis, and podocyte loss in multiple animal models of diabetes ( i.e ., streptozotocin injection, db/db, and high-fat diet feeding). RNA-sequencing of ROCK2-null podocytes provided initial evidence suggesting ROCK2 as a regulator of cellular metabolism. In particular, ROCK2 serves as a suppressor of peroxisome proliferator-activated receptors α (PPARα), which rewires cellular programs to negatively control the transcription of genes involved in fatty acid oxidation and consequently induce podocyte apoptosis. These data establish ROCK2 as a nodal regulator of podocyte energy homeostasis and suggest this signaling pathway as a promising target for the treatment of diabetic podocytopathy. ROCK2 is found to be activated in 3 diabetic models and patients with diabetes. ROCK2 deletion in podocytes protects against diabetic kidney injury, with the beneficial effect of ROCK2 inhibition observed due to rescued PPARα signaling, leading to a recovery of fatty acid metabolism.