The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats

This study aimed to investigate the effect of the Rho-kinase inhibitor fasudil on the development of diabetic nephropathy and clarify a contribution of the Rho/Rho-kinase pathway to the pathogenesis of diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats with an intraperitoneal injection of streptozotocin. Animals were then divided into the following 4 groups; normal control rats, diabetic rats, diabetic rats administered fasudil orally and diabetic rats administered fluvastatin (3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, statin) orally. After 1 month of treatment, neither fasudil nor statin had any influence on blood glucose or blood pressure in diabetic rats. While urinary excretion of albumin and 8-hydroxydeoxyguanosine (8-OHdG) was increased in diabetic rats, both of these increases were abolished by fasudil and statin. Rho activity was enhanced in the renal cortex of diabetic rats compared to normal controls, and this enhancement was abolished by statin treatment. Expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) mRNA was up-regulated in the renal cortex of diabetic rats, and this was abolished by fasudil as well as statin. Expression of NOX4 mRNA (catalytic subunit of NAD(P)H oxidase) was up-regulated in the renal cortex of diabetic rats, an effect which was also abolished by fasudil as well as statin. The present study demonstrates that the Rho/Rho-kinase pathway is involved in up-regulation of TGF-beta, CTGF and NAD(P)H oxidase in diabetic kidney. We conclude that suppression of the Rbo/Rho-kinase pathway could be a new strategy for the treatment of diabetic nephropathy. (C) 2007 Elsevier B.V. All rights reserved.