Rho kinase inhibition in diabetic kidney disease

Abstract

Small GTPases of the Rho family and their down-stream effectors Rho associated kinases (ROCKs) are the molecules that converge a spectrum of 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 kidney disease (DKD). Studies in models of type 1 and type 2 diabetes have indicated blood pressure-independent nephroprotective actions of ROCKi in DKD. The underlying mechanisms include attenuation of diabetes-induced increases in renal expression of prosclerotic cytokines and extracellular matrix, anti-oxidant effects and protection of mitochondrial function, resulting in slower development of glomerulosclerosis and interstitial fibrosis. The studies have also shown antiproteinuric effects of ROCKi that could be related to reductions in permeability of the glomerular barrier and beneficial effects on podocytes. Glomerular haemodynamic mechanisms might also be involved. Despite remaining questions in this field, such as the effects in podocytes later in the course of DKD, specificity of currently available ROCKi, or the roles of individual ROCK isoforms, recent evidence in experimental diabetes suggests that ROCKi might in future broaden the spectrum of treatments available for patients with DKD. This is supported by the evidence generated in models of non-diabetic kidney disease and in clinical studies in patients with various cardiovascular disorders.