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.
Nemoto
T
T
Division of Nephrology, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota, USA.
Burne
M J
MJ
Daniels
F
F
O'Donnell
M P
MP
Crosson
J
J
Berens
K
K
Issekutz
A
A
Kasiske
B L
BL
Keane
W F
WF
Rabb
H
H
D058186:Acute Kidney Injury / Q000401:mortality / Q000503:physiopathology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018791:CD4 Lymphocyte Count; D019040:E-Selectin / Q000276:immunology; D007150:Immunohistochemistry; D007511:Ischemia / Q000150:complications* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000494:pharmacology*; D019007:P-Selectin / Q000276:immunology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D019087:Selectins / Q000187:drug effects*
D000906:Antibodies; D001713:Biphenyl Compounds; D019040:E-Selectin; D008362:Mannosides; D019007:P-Selectin; D019087:Selectins; C108700:bimosiamose disodium; D009195:Peroxidase; D008358:Mannose