Rho-associated kinases (ROCK) are activated in the kidney as well as in cultured cells of diabetic models and have been implicated in renal pathophysiology. To explore whether inhibition of ROCK is protective, we studied its role in a model of accelerated
diabetic nephropathy where uninephrectomized rats were made diabetic by
streptozotocin. After establishing diabetes, rats were treated with the ROCK inhibitor
fasudil continuously or for the final 6 weeks of an 18-week experimental period. The results were compared to similar rats given
losartan, an established treatment of clinical and experimental
diabetic nephropathy, or a combination of both agents. Vehicle-treated diabetic and non-diabetic uninephrectomized rats served as controls. Diabetes resulted in a rapid development of
albuminuria, higher glomerulosclerosis and interstitial
fibrosis scores, lower glomerular filtration rates, and increased expression of several molecular markers of
diabetic nephropathy. Eighteen weeks of
fasudil treatment reduced renal ROCK activity, and ameliorated diabetes-induced structural changes in the kidney and expression of the molecular markers in association with a modest anti-proteinuric effect but no change in blood pressure. Late intervention with
fasudil reduced glomerulosclerosis, but did not influence
proteinuria. Most effects of
fasudil were comparable to those of
losartan, although
losartan lowered blood pressure and further lowered
proteinuria. The combination of both treatments was no different than
losartan alone. Thus, ROCK inhibition protected the kidney from
diabetic nephropathy even though it did not reduce the blood pressure.