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

Takashi Nemoto, Melissa J. Burne, Frank Daniels, Michael P. O’donnell, John Crosson, Kurt Berens, Andrew Issekutz, Bertram L. Kasiske, William F. Keane, Hamid Rabb

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81 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)2205-2214
Number of pages10
JournalKidney international
Volume60
Issue number6
DOIs
StatePublished - 2001

Keywords

  • Cold kidney storage
  • Delayed graft function
  • Disease models
  • Kidney failure
  • Leukocytes
  • Renal artery clamping
  • Transplantation

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    Nemoto, T., Burne, M. J., Daniels, F., O’donnell, M. P., Crosson, J., Berens, K., Issekutz, A., Kasiske, B. L., Keane, W. F., & Rabb, H. (2001). Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure. Kidney international, 60(6), 2205-2214. https://doi.org/10.1046/j.1523-1755.2001.00054.x