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

Abstract

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.

• Authors: T Nemoto, M J Burne, F Daniels, M P O'Donnell, J Crosson, K Berens, A Issekutz, B L Kasiske, W F Keane, H Rabb
• Journal: Kidney international (Kidney Int) Vol. 60 Issue 6 Pg. 2205-14 (Dec 2001) ISSN: 0085-2538 [Print] United States
• PMID: 11737594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies
• Biphenyl Compounds
• E-Selectin
• Mannosides
• P-Selectin
• Selectins
• bimosiamose disodium
• Peroxidase
• Mannose

Topics

• Acute Kidney Injury (mortality, physiopathology)
• Animals
• Antibodies (pharmacology)
• Biphenyl Compounds (pharmacology)
• CD4 Lymphocyte Count
• E-Selectin (immunology)
• Immunohistochemistry
• Ischemia (complications, physiopathology)
• Kidney (drug effects, pathology, physiopathology)
• Kidney Tubules (pathology)
• Male
• Mannose (analogs & derivatives)
• Mannosides (pharmacology)
• P-Selectin (immunology)
• Peroxidase (metabolism)
• Rats
• Rats, Sprague-Dawley
• Renal Circulation
• Selectins (drug effects)