Endogenous urokinase lacks antifibrotic activity during progressive renal injury

Ikuyo Yamaguchi, Jesus M. Lopez-Guisa, Xiaohe Cai, Sarah J. Collins, Daryl M. Okamura, Allison A. Eddy

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Interstitial fibrosis is a universal feature of progressive kidney disease. Urokinase-type plasminogen activator (uPA) is thought to participate for several reasons: 1) uPA is produced predominantly in kidney, 2) its inhibitor plasminogen activator inhibitor-1 (PAI-1) is a strong promoter of interstitial fibrosis, whereas its receptor (uPAR) attenuates renal fibrosis, 3) uPA reduces fibrosis in liver and lung, and 4) uPA can activate hepatocyte growth factor (HGF), a potent antifibrotic growth factor. The present study tested the hypothesis that endogenous uPA reduces fibrosis severity by investigating the unilateral ureteral obstruction (UUO) model in wild-type (WT) and uPA-/-mice. Several outcomes were measured: renal collagen 3-21 days after UUO, macrophage accumulation (F4/80 Western blotting), interstitial myofibroblast density (α-smooth muscle actin immunostaining), and tubular injury (E-cadherin and Ksp-cadherin Western blotting). None of these measures differed significantly between WT and uPA-/- mice. uPA genetic deficiency was not associated with compensatory changes in renal uPAR mRNA levels, PAI-1 protein levels, or tissue plasminogen activator activity levels after UUO. Despite the known ability of uPA to activate latent HGF, immunoblotting failed to detect significant differences in levels of the active HGF α-chain and phosphorylated cMET (the activated HGF receptor) between the WT and uPA-/- groups. These findings suggest that the profibrotic actions of PAI-1 are uPA independent and that an alternative pathway must activate HGF in kidney. Finally, these results highlight a significant organ-specific difference in basic fibrogenic pathways, as enhanced uPA activity has been reported to attenuate pulmonary and hepatic fibrosis.

Original languageEnglish (US)
Pages (from-to)F12-F19
JournalAmerican Journal of Physiology - Renal Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 2007
Externally publishedYes

Keywords

  • Renal interstitial fibrosis
  • Serine protease
  • Unilateral ureteral obstruction

ASJC Scopus subject areas

  • Physiology
  • Urology

Fingerprint Dive into the research topics of 'Endogenous urokinase lacks antifibrotic activity during progressive renal injury'. Together they form a unique fingerprint.

  • Cite this