Chronic renal failure (CRF) is a progressive disease accompanied by endothelial dysfunction and a high rate of vascular co-morbidity. ACE inhibition slows disease progression and attenuates radical formation and matrix deposition. We aimed on dissecting potential effects of angiotensin II in particular of the downstream effector GTPases Rac1 and RhoA with the aid of pharmacological inhibitors in the 5/6 nephrectomy (5/6Nx) model of CRF in mice. SV-129 mice were subjected to 5/6Nx and subgroups were treated with the ACE-inhibitor ramipril (40 mg/L), the statin rosuvastatin (10 mg/kg), the Rho-kinase-inhibitor SAR407899 (10 mg/kg) or the Rac-inhibitor EHT1864 (40 mg/kg) for 8 weeks. Subsequently, albuminuria and vascular function in isolated aortic rings was determined by ELISA and an organ chamber setup, respectively. The 5/6Nx model induced substantial hypertension and albuminuria in vivo. Aortic rings from 5/6Nx mice exhibited attenuated acetylcholine (ACh)- induced endothelium-dependent relaxation. In 5/6Nx mice treatment with the Rac-inhibitor, the Rho-kinase-inhibitor or the ACE-inhibitor the ACh-induced relaxation was significantly greater and not different from that observed in sham- treated animals. In contrast, responses in statin treated animals were identical to those observed in the placebo group. The contractile response to the NO synthase inhibitor L-NAME, which is a measure for basal NO availability was similarly affected. Direct application of the Rac1 inhibitor to aortic ring of control mice unexpectedly rather attenuated endothelium- dependent relaxation suggesting that Rac1 under physiological conditions positively contributes to endothelium-dependent relaxation. These observations indicate that an activation of Rac1 and RhoA contribute to the progression of renal failure. These GTPases might therefore be attractive new pharmacological targets in the treatment of the disease.