Plasminogen directs the pleiotropic effects of uPA in liver injury and repair.
The urokinase-type plasminogen activator (uPA) plays a central role in liver repair. Nevertheless, the hepatic overexpression of uPA results in panlobular injury and neonatal mortality. Here, we define the molecular mechanisms of liver injury and explore whether uPA can regulate liver repair independently of plasminogen. To address the hypothesis that the liver injury in transgenic mice results from the intracellular activation of plasminogen by transgene-derived uPA (uPAT), we generated mice that overexpress uPAT and lack functional plasminogen (uPAT-Plg(-)). In these mice, loss of plasminogen abolished the hepatocyte-specific injury and prevented the formation of regenerative nodules displayed by uPAT littermates. Despite the increased expression of hepatic uPA, livers of uPAT-Plg(-) mice were unable to clear necrotic cells and restore normal lobular organization after an acute injury. Notably, high levels of circulating uPA in uPAT-Plg(-) mice did not prevent the long-term extrahepatic abnormalities previously associated with plasminogen deficiency. These data demonstrate that plasminogen directs the hepatocyte injury induced by uPAT and mediates the reparative properties of uPA in the liver.
Currier
Angela R
AR
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Research Foundation and Department of Pediatrics, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Sabla
Gregg
G
Locaputo
Stephanie
S
Melin-Aldana
Hector
H
Degen
Jay L
JL
Bezerra
Jorge A
JA
D000818:Animals; D015152:Blotting, Northern; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects; D007202:Indicators and Reagents; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D010958:Plasminogen / Q000235:genetics* / Q000502:physiology*; D010960:Plasminogen Activators / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000502:physiology*
D007202:Indicators and Reagents; D010958:Plasminogen; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator