Plasminogen directs the pleiotropic effects of uPA in liver injury and repair

Angela R. Currier, Gregg Sabla, Stephanie Locaputo, Hector Melin-Aldana, Jay L. Degen, Jorge A. Bezerra*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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 litter-mates. 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.

Original languageEnglish (US)
Pages (from-to)G508-G515
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume284
Issue number3 47-3
DOIs
StatePublished - Mar 1 2003

Keywords

  • Hepatocyte
  • Proliferation
  • Regeneration
  • Tissue remodeling
  • Urokinase

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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