OBJECTIVE-RhoA, a small GTPase protein, and its immediate downstream target, Rho kinase (ROCK), control a wide variety of signal transduction pathways. Recent studies have shown that fasudil, a selective ROCK inhibitor, may play a pivotal role in a number of pathological conditions, ranging from cardiovascular diseases to pulmonary hypertension and erectile dysfunction. Considerable evidence suggests that some of the beneficial effects of statins may also stem from their modulatory effects on RhoA/ROCK signaling. In the current study, we hypothesized that pharmacological blockade of the RhoA/ROCK pathway with either fasudil or simvastatin would ameliorate progression of diabetic nephropathy. RESULTS-The kidney cortices of untreated db/db mice displayed increased ROCK activity compared with db/m mice. The fasudil-treated mice exhibited a significant reduction in ROCK activity, albuminuria, glomerular collagen IV accumulation, and urinary collagen IV excretion compared with untreated db/db mice. Interestingly, blood glucose was unaffected by fasudil administration. Treatment with simvastatin significantly attenuated RhoA activation in the kidney cortices of db/db mice and resulted in a significant reduction of albuminuria and mesangial matrix expansion. RESEARCH DESIGN AND METHODS-InCONCLUSIONS-Based on these results, we propose that RhoA/ROCK blockade constitutes a novel approach to the treatment of diabetic nephropathy. Our data also suggest a critical role for RhoA/ROCK activation in the pathogenesis of diabetic nephropathy. Diabetes 57:714-723, 2008 T he Rho family of small GTPases are 20-to 40-kDa monomeric G proteins that regulate a number of cell functions, including cytoskeletal reorganization, cell motility, and gene expression (1). They cycle between two conformational states: an active GTPbound state and an inactive GDP-bound state (2). One of the best recognized members of the Rho GTPase family is RhoA. Rho kinase (ROCK), a downstream effector of RhoA, is a serine/threonine kinase of ϳ160 kDa that exists in two isoforms in mammals: ROCK1 and ROCK2 (3). ROCK is comprised of an amino-terminal kinase domain, followed by a coiled-coil region that contains the -binding domain. The carboxy-terminal consists of a plexstrinhomology domain, which contains an internal cysteinerich domain. ROCK1 and ROCK2 are highly homologous, sharing an identity of 65% in their overall amino acid sequences and 92% in their kinase domains.The RhoA/ROCK pathway has recently received considerable attention for its involvement in a wide variety of pathological states ranging from cardiovascular disease and pulmonary hypertension to Alzheimer's disease and glaucoma (4 -7). A growing body of evidence also suggests that the RhoA/ROCK pathway may have renomodulatory effects. Indeed, several recent studies have proposed that RhoA/ROCK may play an important role in renal fibrosis by enhancing signaling pathways involving transforming growth factor-␤, angiotensin II, and nuclear factor-B (8 -10). Furthermore, since the discovery of fasudi...