title: Platelets are relevant mediators of renal injury induced by primary endothelial lesions.
abstract: Several studies have suggested a prominent (pro)inflammatory and harmful role of platelets in renal disease, and newer work has also demonstrated platelet release of proangiogenic factors. In the present study, we investigated the role of platelets in a mouse model of selective endothelial cell injury using either platelet depletion or the pharmacological P2Y12 receptor blocker clopidogrel as an interventional strategy. The concanavalin A/anti-concanavalin A model was induced in left kidneys of C57bl/6J wild-type mice after initial platelet depletion or platelet-inhibiting therapy using clopidogrel. FACS analysis of glycoprotein IIb/IIIa/P-selectin double-positive platelets and platelet-derived microparticles demonstrated relevant platelet activation after the induction of selective endothelial injury in mice. Enhanced platelet activation persisted for 5 days after disease induction and was accompanied by increased amounts of circulating platelet-derived microparticles as potential mediators of a prolonged procoagulant state. By immunohistochemistry, we detected significantly reduced glomerular injury in platelet-depleted mice compared with control mice. In parallel, we also saw reduced endothelial loss and a consequently reduced repair response as indicated by diminished proliferative activity. The P2Y12 receptor blocker clopidogrel demonstrated efficacy in limiting platelet activation and subsequent endothelial injury in this mouse model of renal microvascular injury. In conclusion, platelets are relevant mediators of renal injury induced by primary endothelial lesions early on, as demonstrated by platelet depletion as well as platelet inhibition via the P2Y12 receptor. While strategies to prevent platelet-endothelial interactions have shown protective effects, the contribution of platelets during renal regeneration remains unknown.
authors.affiliation: Division of Nephrology, Department of Internal Medicine III, Technische Universitaet Dresden, Dresden, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Schwarzenberger
authors.affiliation: Division of Nephrology, Department of Internal Medicine III, Technische Universitaet Dresden, Dresden, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Sradnick
authors.affiliation: Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York;
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Lerea
authors.affiliation: Renal Research Institute, New York Medical College, Valhalla, New York; and.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
authors.affiliation: Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Division of Nephrology, Department of Internal Medicine III, Technische Universitaet Dresden, Dresden, Germany;
authors.forename: Christian P M
authors.initials: CP
authors.lastname: Hugo
authors.affiliation: Division of Nephrology, Department of Internal Medicine III, Technische Universitaet Dresden, Dresden, Germany; bernd.hohenstein@uniklinikum-dresden.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hohenstein
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D000077144:Clopidogrel; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D019007:P-Selectin; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: clopidogrel; platelet microparticles; platelets; renal microvascular endothelial injury; thrombotic microangiopathy
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