Role of Rho Kinases in Diabetic Nephropathy

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DESCRIPTION (provided by applicant): Rho kinase (ROCK) is a serine/threonine protein kinase which functions as one of the downstream effectors for the small G-protein RhoA. The RhoA/ROCK pathway has an important role in mediating various cellular processes, including cytoskeletal remodeling, cell proliferation, and gene expression. More recently, the RhoA/ROCK pathway has emerged as a promising target in the treatment of coronary vasospasm, stroke, erectile dysfunction, and hypertension. In this proposal, we argue that ROCK also plays a critical role in the pathogenesis of diabetic nephropathy (DN) via its involvement in modulating the reactive oxygen species (ROS) signaling pathway. Our hypothesis is based on several novel observations: 1) RhoA/ROCK pathway is involved in glucose-induced signaling (Danesh FR et al. Proc. Natl. Acad. Sci. 2002), 2) Blockade of ROCK ameliorates progression of DN in the db/db model of type 2 diabetes (Kolavennu V et al. Diabetes 2007), and 3) our preliminary data suggesting that ROCK activation plays a pivotal role in both mitochondrial and NADPH redox signaling. Based upon these initial observations, we now propose an integrated in vitro and in vivo approach to test three specific aims. Aim 1: To test the hypothesis that at the cellular level, ROCK mediates the cross-talk between mitochondrial- and NADPH-derived ROS overproduction in the diabetic milieu. Aim 2: To test the hypothesis that selective inhibition of ROCK in the experimental models of type 1 and type 2 diabetes ameliorates the progression of DN by inhibiting ROCK-mediated ROS production. Aim 3: To test the effect of tissue-specific conditional gene targeting of ROCK in DN. The findings of this application will provide a significant advance in three aspects: first, the successful completion of this proposal is not only relevant to kidney research, but it will also provide a framework for understanding the spatial and temporal behavior of redox signaling. Second, it will assess the role of RhoA/ROCK signaling in the kidney. And third, it will lead to development of novel therapeutic strategies in DN.