CYCLIC RGD PEPTIDES AMELIORATE ISCHEMIC ACUTE-RENAL-FAILURE IN RATS

Renal tubular obstruction is an important contributor to the pathophys iology of acute renal failure. Based on the previous findings of the r ole played by arginine-glycine-aspartic acid (RGD) recognizing integri ns in tubular obstruction, this study examined the effect of RGD pepti des on the course of ischemic acute renal failure in rats. For in vivo studies, animals were subjected to 45 minutes of unilateral renal isc hemia with contralateral nephrectomy, and cyclic RGD peptides or a lin ear biotinylated RGD peptide were injected systemically after the rele ase of renal artery clamp. In vitro studies compared the potency of th e peptides in inhibiting BS-C-1 cell-matrix and cell-cell adhesion. Tw o 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 in hibiting cell-matrix adhesion, a single systemic administration of eit her peptide improved creatinine clearance postoperatively and accelera ted recovery of renal function with a rank order: cyclic RGDDFV greate r than or equal to RGDDFLG much greater than RDADFV (inactive control) . These findings represent the first in vivo demonstration of the effe ctiveness of cyclic RGD peptides in ameliorating ischemic acute renal failure, and suggest that in this setting RGD peptides predominantly i nhibit cell-cell adhesion, whereas inhibition of cell-matrix adhesion is of lesser significance.