title: Activation of parenchymal CD47 promotes renal ischemia-reperfusion injury.
abstract: Ischemia-reperfusion injury (IRI) contributes to decreased allograft function and allograft rejection in transplanted kidneys. Thrombospondin-1 is a stress protein typically secreted in response to hypoxia and the ligand activator for the ubiquitously expressed receptor CD47. The function of activated CD47 in IRI remains completely unknown. Here, we found that both CD47 and its ligand thrombospondin-1 were upregulated after renal IRI in mice. CD47-knockout mice were protected against renal dysfunction and tubular damage, suggesting that the development of IRI requires intact CD47 signaling. Chimeric CD47-knockout mice engrafted with wild-type hematopoietic cells had significantly lower serum creatinine and less tubular damage than wild-type controls after IRI, suggesting that CD47 signaling in parenchymal cells predominantly mediates renal damage. Treatment with a CD47-blocking antibody protected mice from renal dysfunction and tubular damage compared with an isotype control. Taken together, these data imply that CD47 on parenchymal cells promotes injury after renal ischemia and reperfusion. Therefore, CD47 blockade may have therapeutic potential to prevent or suppress ischemia-reperfusion-mediated damage.
authors.affiliation: Division of Pulmonary Allergy and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine, E1240 Biomedical Science Tower, Room E1258, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Rogers
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D051928:CD47 Antigen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D019700:Thrombospondin 1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; D016207:Cytokines; D017382:Reactive Oxygen Species; D019700:Thrombospondin 1; D003404:Creatinine