Endothelial dysfunction contributes significantly to acute renal failure (ARF) during inflammatory diseases including septic shock. Previous studies have shown that activated Protein C (APC) exhibits anti-inflammatory properties and modulates endothelial function. Therefore, we investigated the effect of APC on ARF in a rat model of endotoxemia. Rats subjected to lipopolysaccharide (LPS) treatment exhibited ARF as illustrated by markedly reduced peritubular capillary flow and increased serum BUN levels. Using quantitative two-photon intravital microscopy, we observed that at 3 hours post-LPS treatment, rat APC (0.1 mg/kg, i.v. bolus) significantly improved peritubular capillary flow [288±15 µm/sec (LPS) vs. 734±59 µ m/sec (LPS+APC), p=0.0009], and reduced leukocyte adhesion [p=0.003] and rolling [p=0.01] in comparison to the LPS-treated group. Additional experiments demonstrated that APC treatment significantly improved renal blood flow and reduced serum BUN levels when compared to 24h post-LPS treatment. Biochemical analysis revealed that APC down-regulated inducible nitric oxide synthase (iNOS) mRNA levels and NO by-products in the kidney. In addition, APC modulated the renin-angiotensin system by reducing mRNA expression levels of angiotensin converting enzyme-1 (ACE1), angiotensinogen and increasing ACE2 mRNA levels in the kidney. Further, APC significantly reduced angiotensin II levels in the kidney in comparison to the LPS-treated group. Taken together, these data suggest that APC can suppress LPS-induced ARF by modulating factors involved in vascular inflammation, including down-regulation of renal iNOS and angiotensin II systems. Further, the data suggest a potential therapeutic role for APC in the treatment of ARF.