Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure

Background. The pathophysiologic and potential therapeutic role of selectin s in renal ischemia-reperfusion injury (IRI) is not fully understood, due i n part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecu le (TBC-1269) would improve the course of renal IRI by overcoming redundanc y issues. This was investigated in a rat model of renal IRI. Methods. Rats were treated with TBC-1269 either during or post-IRI. The eff ects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes cl amping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histologic al injury and mortality were assessed. Results. Rats treated with TBC-1269 during moderate IRI showed significantl y reduced serum creatinine (S-Cr) and tubular necrosis post-ischemia compar ed to control animals. By contrast, delayed treatment (post-IRI) did not sh ow a reduction in S-Cr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with mo derate IRI and treated with the combination of anti-E- and anti-P-selectin antibodies showed significantly reduced S-Cr compared to control rats at 24 hours post-ischemia. Conclusions. Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of tr eatment is crucial to success.