Platelet, but not endothelial, P-selectin is critical for neutrophil-mediated acute postischemic renal failure.
In a neutrophil-dependent model of acute postischemic renal failure (APRF), eliminating or blocking P-selectin reduces postischemic neutrophil infiltration and preserves kidney function. This study was designed to identify the role of platelet vs. endothelial P-selectin in APRF. Using wild-type (wt) and P-selectin-deficient (P-/-) mice, we generated chimeric mice by bone marrow transplantation. Chimeric mice exclusively expressed either platelet (Plt-P) or endothelial P-selectin (EC-P). APRF was induced by bilateral renal ischemia in situ (32 min), followed by reperfusion; 48 h after reperfusion, EC-P had significantly lower creatinine concentrations (twofold over sham) than Plt-P (eightfold over sham). Compared with wt, protection from renal failure in EC-P was similar to that observed in P-/-. Plt-P and EC-P demonstrated similar overall postischemic neutrophil infiltration as measured by renal myeloperoxidase activity. However, Plt-P showed massive neutrophil infiltration into outer and inner medulla, similar to that in wt. EC-P had only patchy, more diffuse neutrophil influx. Our study identifies platelet P-selectin as crucial for postischemic neutrophil recruitment into outer and inner medulla, which is detrimental to the development of APRF. This suggests that novel therapeutic strategies for postischemic organ failure could be aimed at neutrophil-platelet interactions.
Singbartl
K
K
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
Forlow
S B
SB
Ley
K
K
D058186:Acute Kidney Injury / Q000209:etiology* / Q000503:physiopathology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D003404:Creatinine / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020556:Neutrophil Infiltration / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology; D019007:P-Selectin / Q000097:blood / Q000235:genetics / Q000502:physiology*; D010976:Platelet Count
D019007:P-Selectin; D003404:Creatinine