Authors: (Toshio Nishikimi - Dept. of Hypertension and Cardiorenal Medicine, Dokkyo Medical Univ., Mibu, Japan)
Abstract: Recent studies demonstrated the importance of small GTP binding protein in physiological function. Rho, a member of small GTP binding protein, is known to function as a molecular switch in various cellular functions, including contraction, actin cytoskeleton organization, cell adhesion and motility, proliferation, cytokinesis, and gene expression. Among the Rho effectors, the cellular function and signal transduction of Rho-kinase have been extensively studied. However, the information about in vivo function is still limited until a specific inhibitor of Rho-kinase such as Y-27632 and fasudil was discovered. Rho-kinase inhibitor is a very powerful tool for examining the role of the Rho/Rho-kinase pathway in vitro and in vivo. Recent studies have demonstrated that Rho/Rho-kinase pathway is involved in the pathogenesis of various cardiovascular diseases such as arteriosclerosis, hypertension, angina pectoris, myocardial infarction, and pulmonary hypertension. However, there are few studies, which investigated the role of Rho/Rho-kinase in renal disease. Here we review the information about the therapeutic importance of the Rho/Rho-kinase pathway in renal disease. Specifically, we describe the recent our results about beneficial effect of Rho-kinase inhibitor on the glomerulosclerosis in hypertensive nephropathy. Our results suggest that chronic inhibition of Rho-kinase pathway may be a new therapeutic approach for the hypertensive glomerulosclerosis. Our results also suggest that the possible mechanism of renoprotective effect of Rho-kinase inhibitor is mediated via many pathways, including inhibition of extracellular matrix gene expression, monocytes/macrophages infiltration, and oxidative stress, and upregulation of eNOS gene expression.