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

Kidney Int. 2001 Dec;60(6):2205-14. doi: 10.1046/j.1523-1755.2001.00054.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


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