Background. The pathophysiologic and potential therapeutic role of selectins in renal ischemia-reperfusion injury (IRI) is not fully understood, due in part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecule (TBC-1269) would improve the course of renal IRI by overcoming redundancy issues. This was investigated in a rat model of renal IRI. Methods. Rats were treated with TBC-1269 either during or post-IRI. The effects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes clamping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histological injury and mortality were assessed. Results. Rats treated with TBC-1269 during moderate IRI showed significantly reduced serum creatinine (SCr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in SCr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with moderate IRI and treated with the combination of antiE- and anti-P-selectin antibodies showed significantly reduced SCr 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 treatment is crucial to success.
Bibliographical noteFunding Information:
This work was supported by grants from the American Heart Association, National Kidney Foundation, National Institutes of Health R0-1 DK54770, and Hermundslie Trust to H.R, and a National Kidney Foundation Post Doctoral Fellowship Award to M.B. The authors would like to thank Mr. Robert Geske from Baylor College of Medicine for his assistance with the immunostaining procedure.
- Cold kidney storage
- Delayed graft function
- Disease models
- Kidney failure
- Renal artery clamping