title: Human activated protein C attenuates both hepatic and renal injury caused by hepatic ischemia and reperfusion injury in mice.
abstract: Hepatic ischemia and reperfusion (IR) injury is a major clinical problem often leading to acute kidney injury characterized by early endothelial cell apoptosis, subsequent neutrophil infiltration, proximal tubule necrosis/inflammation, impaired vascular permeability, and disintegration of the proximal tubule filamentous actin cytoskeleton. Activated protein C is a major physiological anticoagulant with anti-inflammatory and anti-apoptotic activities in endothelial cells. Here we tested if activated protein C would attenuate hepatic and renal injury caused by hepatic ischemia and reperfusion. Both liver and kidney injury were significantly reduced when activated protein C was given immediately before and 2 h after liver reperfusion, in that there was reduced renal endothelial and hepatocyte apoptosis, as well as reduced hepatic and renal tubular necrosis. Further, the administration of activated protein C also reduced the expression of several pro-inflammatory genes, liver and kidney filamentous-actin degradation, and neutrophil infiltration, and resulted in better preservation of vascular permeability of both the liver and kidney than is normally seen after liver ischemia and reperfusion. These protective effects of activated protein C were due to protease-activated receptor-1 modulation since administration of a selective receptor antagonist dose-dependently inhibited its ameliorative effects in both organs after liver ischemia and reperfusion. Our results suggest the powerful multi-organ protective effects of activated protein C may improve outcome in those patients at significant risk of developing acute kidney injury following liver ischemia and reperfusion during transplantation.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032-3784, USA.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.forename: Sean W C
authors.initials: SW
authors.lastname: Chen
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D042783:Endothelial Cells / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D007249:Inflammation; D007674:Kidney Diseases / Q000473:pathology / Q000517:prevention & control*; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D020011:Protective Agents; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D044463:Receptor, PAR-1 / Q000502:physiology*; D015427:Reperfusion Injury / Q000188:drug therapy*
chemical_list: D020011:Protective Agents; D011486:Protein C; D044463:Receptor, PAR-1