Role of Rho Kinase in Diabetic Nephropathy

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DESCRIPTION (provided by applicant): Diabetic nephropathy represents the primary cause of end stage renal disease (ESRD) in the US, underscoring the need for innovative therapies for preventing its progression. We are interested in understanding the cellular and molecular mechanisms that govern mitochondrial dysfunction in the diabetic milieu with the expectation that understanding of these processes will expose potential disease mechanisms and therapeutic targets in diabetic nephropathy. The present proposal is based on our recent published observation, indicating that ROCK1-mediated mitochondrial fragmentation is essential for prompting mitochondrial dysfunction in podocytes and glomerular endothelial cells in the diabetic milieu. A detailed understanding of mechanisms that govern mitochondrial fission in the kidney remains incomplete and therapeutic targets based on these mechanisms do not exist. Because dynamin-related protein-1 (Drp1) is an integral part in regulating mitochondrial fission, we have focused on investigating the functions of ROCK1 on Drp1 translocation to the mitochondria resulting in mitochondrial fragmentation and cell apoptosis. We have been guided by our recent published observations that ROCK1 mediates high glucose-induced mitochondrial fragmentation by promoting Drp1 recruitment to the mitochondria. Deletion of ROCK1 in db/db diabetic mice prevented mitochondrial fission, whereas podocyte-specific constitutively active (cA)-ROCK1 mice exhibited increased mitochondrial fission. Importantly, we found that ROCK1 triggers mitochondrial fission by phosphorylating Drp1 at serine 600 residue. These findings provide compelling initial evidence into the unexpected role of ROCK1 in a signaling cascade that regulates mitochondrial dynamics, and represents a therapeutic target that might be useful in preventing diabetic kidney disease. Given these results and additional preliminary data presented in this application, this project will address the hypothesis that phosphorylation of Drp1 is a key feature of mitochondria dysfunction in diabetic nephropathy. The results of this study will provide important new insights into the role of mitochondrial morphology in the development of diabetic nephropathy, and may lead to novel therapeutic targets for the future treatment of diabetic kidney disease.