Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. Renal tubular obstruction is an important contributor to the pathophysiology of acute renal failure. Based on the previous findings of the role played by arginine-glycine-aspartic acid (RGD) recognizing integrins in tubular obstruction, this study examined the effect of RGD peptides on the course of ischemic acute renal failure in rats. For in vivo studies, animals were subjected to 45 minutes of unilateral renal ischemia with contralateral nephrectomy, and cyclic RGD peptides or a linear biotinylated RGD peptide were injected systemically after the release of renal artery clamp. In vitro studies compared the potency of the peptides in inhibiting BS-C-1 cell-matrix and cell-cell adhesion. Two novel cyclic RGD peptides utilized in these studies showed different inhibitory potency in preventing cell-matrix adhesion: cyclic RGDDFV was a highly potent in vitro inhibitor of BS-C-1 cell-matrix adhesion, whereas cyclic RGDDFLG was less potent. In cell-cell adhesion assays, however, both peptides were equipotent. Despite the differences in inhibiting cell-matrix adhesion, a single systemic administration of either peptide improved creatinine clearance postoperatively and accelerated recovery of renal function with a rank order: cyclic RGDDFV ≥ RGDDFLG > RDADFV (inactive control). These findings represent the first in vivo demonstration of the effectiveness of cyclic RGD peptides in ameliorating ischemic acute renal failure, and suggest that in this setting RGD peptides predominantly inhibit cell-cell adhesion, whereas inhibition of cell-matrix adhesion is of lesser significance.