[HTML][HTML] Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure
T Nemoto, MJ Burne, F Daniels, MP O'Donnell… - Kidney international, 2001 - Elsevier
T Nemoto, MJ Burne, F Daniels, MP O'Donnell, J Crosson, K Berens, A Issekutz, BL Kasiske…
Kidney international, 2001•ElsevierSmall molecule selectin ligand inhibition improves outcome in ischemic acute renal failure.
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 …
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 …
Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure.
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 anti-E- 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.
Elsevier