Platelet, but not endothelial, P‐selectin is critical for neutrophil‐mediated acute postischemic renal failure

Abstract

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.

Measuring and interpreting platelet-leukocyte aggregates

“…Accordingly, some clinical studies (using only a small patient cohort, however) show beneficial effects of anti-platelet therapy in glomerulonephritis patients by reducing circulating platelet aggregates, albuminuria and/or glomerular filtration rate (109–113) and anti-platelet drugs are indeed commonly prescribed in Japanese hospitals to patients with IgA nephropathy (114). The contribution of platelets in the induction of renal inflammation via direct interactions with leukocytes is further supported by the requirement of platelet P-selectin for neutrophil recruitment and/or neutrophil-mediated injury in experimental acute postischemic renal failure (115) and glomerulonephritis (21,22). Neutrophil-depletion on the other hand prevented platelet accumulation within glomerular capillaries in a model of immune-complex-induced glomerulonephritis (22), emphasising the importance of the interplay between platelets and neutrophils during this disease.…”

Integrin Regulation during Leukocyte Recruitment

“…CD8 + T cells roll on TNF-a-and IFN-g-treated vessels in a VLA-4-dependent manner (28). VLA-4 seems to be the predominant integrin mediating lymphocyte rolling (29); however, physiological relevance of monocyte and T cell rolling for recruitment to peripheral tissues and involved signaling pathways affecting integrin affinity and avidity are still unclear.…”

Combined anticoagulant and antiselectin treatments prevent lethal intravascular coagulation

“…This procedure routinely produces mice with more than 95% platelets of the donor phenotype 4 to 5 weeks after transplantation. 23 Transplantation of P-selectin-deficient bone marrow into wild-type recipients produced mice with P-selectin-positive endothelium and P-selectin-negative platelets. Transplantation of wild-type bone marrow into P-selectin-deficient recipients produced mice with P-selectin-positive platelets and P-selectin-negative endothelium.…”