Rho kinase inhibition in diabetic nephropathy

Abstract

The Rho GTPases and their downstream effectors Rho-associated kinases (ROCKs) appear to be the molecules that converge numerous pathophysiological signals triggered by the diabetic milieu and represent promising molecular targets for nephroprotective treatment in diabetes. The review discusses recent studies exploring the consequences of diabetes-induced Rho-ROCK activation in the kidney and the effects of ROCK inhibition (ROCKi) in experimental diabetic nephropathy. Recent studies in models of type 1 and type 2 diabetes have indicated blood-pressure-independent nephroprotective actions of ROCKi in diabetic nephropathy. The underlying mechanisms include attenuation of diabetes-induced increases in renal expression of prosclerotic cytokines and extracellular matrix, resulting in slower development of glomerulosclerosis and interstitial fibrosis. The studies have also shown antiproteinuric affects of ROCKi that could be related to reductions in permeability of glomerular barrier and beneficial effects on podocytes. Moreover hemodynamic mechanisms might be also involved. Despite remaining questions in this field, such as the specificity of currently available ROCKi, or the roles of individual ROCK isoforms, recent evidence in experimental diabetes, together with evidence generated in models of nondiabetic kidney disease and in clinical studies in patients with various cardiovascular disorders, suggest that ROCKi might in future broaden the spectrum of treatments available for patients with diabetic nephropathy.