Osteopontin, a secreted glycoprotein has been implicated in several renal pathological conditions such as those due to ureteral obstruction, ischemia, and cyclosporine toxicity. We studied its possible role in angiotensin II-mediated renal injury by infusing wild-type and osteopontin knockout mice with angiotensin II and found that it raised blood pressure and increased urinary albumin/creatinine ratios in both strains of mice. However, while wild-type mice responded to the infusion by macrophage infiltration and increased expression of alpha-smooth muscle actin, fibronectin, and transforming growth factor-beta; the osteopontin knockout mice developed none of these. Further, the knockout mice had increased expression of monocyte chemoattractant protein-1; NADPH oxidase subunits such as NOX2, gp47phox, and NOX4; and plasminogen activator inhibitor-1 compared to the wild type animals. Proximal tubule epithelial cells in culture treated with recombinant osteopontin and angiotensin II had increased alpha-smooth muscle actin and transforming growth factor-beta expression. The effect of angiotensin II was blocked by an antibody to osteopontin. In addition, osteopontin attenuated angiotensin II-induced plasminogen activator inhibitor-1 expression. These studies show that osteopontin is a promoter and an inhibitor of inflammation, oxidative stress, and fibrosis that is capable of modulating angiotensin II-induced renal damage.