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

doi:10.1046/j.1523-1755.2001.00054.x

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

Research output: Contribution to journal › Article › peer-review

97 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 (S_Cr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in S_Cr. 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 S_Cr 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 language	English (US)
Pages (from-to)	2205-2214
Number of pages	10
Journal	Kidney international
Volume	60
Issue number	6
DOIs	https://doi.org/10.1046/j.1523-1755.2001.00054.x
State	Published - 2001

Bibliographical note

Funding 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.

Keywords

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

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title = "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 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.",

keywords = "Cold kidney storage, Delayed graft function, Disease models, Kidney failure, Leukocytes, Renal artery clamping, Transplantation",

author = "Takashi Nemoto and Burne, {Melissa J.} and Frank Daniels and O{\textquoteright}donnell, {Michael P.} and John Crosson and Kurt Berens and Andrew Issekutz and Kasiske, {Bertram L.} and Keane, {William F.} and Hamid Rabb",

note = "Funding 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.",

year = "2001",

doi = "10.1046/j.1523-1755.2001.00054.x",

language = "English (US)",

volume = "60",

pages = "2205--2214",

journal = "Kidney international",

issn = "0085-2538",

publisher = "Elsevier B.V.",

number = "6",

}

TY - JOUR

T1 - Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure

AU - Nemoto, Takashi

AU - Burne, Melissa J.

AU - Daniels, Frank

AU - O’donnell, Michael P.

AU - Crosson, John

AU - Berens, Kurt

AU - Issekutz, Andrew

AU - Kasiske, Bertram L.

AU - Keane, William F.

AU - Rabb, Hamid

N1 - Funding 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.

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - Cold kidney storage

KW - Delayed graft function

KW - Disease models

KW - Kidney failure

KW - Leukocytes

KW - Renal artery clamping

KW - Transplantation

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U2 - 10.1046/j.1523-1755.2001.00054.x

DO - 10.1046/j.1523-1755.2001.00054.x

M3 - Article

C2 - 11737594

AN - SCOPUS:0035191257

SN - 0085-2538

VL - 60

SP - 2205

EP - 2214

JO - Kidney international

JF - Kidney international

IS - 6

ER -

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

Abstract

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