Chronic renal failure is a progressive disease which is maintained by a progressive dysfunction of podocytes followed by renal inflammation and tubulo-interstitial fibrosis. Small GTPases of the Rho family are central cellular signaling molecules which are activated by a multitude of different stimuli and control important cellular functions such as cytoskeletal organization and gene expression. We hypothesized that activation of small GTPases mediates podocyte-dysfunction and promotes progression of renal failure. Stimulation of primary murine podocytes with angiotensin II (AngII), an important progression factor for chronic kidney disease, resulted in a substantial activation of the small GTPase Rac1, a member of the Rho family. Moreover, AngII, as well as other progression factors such as LPS or endothelin, induced an inflammatory activation of podocytes as documented by the induction of IL-6, IL-10 and iNOS. Importantly, inhibition of Rac1 by EHT1864 as well as of by a rhoA-dependent kinase inhibitor, dramatically attenuated these responses. HMG-CoA-reductase inhibitors (statins) mediate parts of their beneficial effects through an inhibition of RhoA and Rac1. Accordingly, Rosuvastatin had a similar effect as inhibition of Rac1 or RhoA. In order to determine the significance of these observations for renal failure, the 5/6 nephrectomy model was used in SV129 mice. In this remnant kidney model we observed a progressive development of hypertension, glomerula dysfunction as characterized by albuminuria as well as structural remodeling determined by kidney histology. Application of the Rac1 as well as RhoA inhibitors had no effect on blood pressure but prevented the progression of kidney disease: In the groups treated with the compounds, development of albuminuria was strongly suppressed and structural remodelling was significantly attenuated. These data suggest that activation of small GTPases importantly contribute to podocytes dysfunction in progressive renal failure. Inhibitors of Rac1 and RhoA may be attractive candidates for the treatment of chronic kidney disease.