PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction

Kidney Int. 2001 Aug;60(2):587-96. doi: 10.1046/j.1523-1755.2001.030002587.x.

Abstract

Background: Progressive renal disease is characterized by the induction of plasminogen activator inhibitor-1 (PAI-1), suggesting that impaired activity of the renal plasmin cascade may play a role in renal fibrosis.

Methods: To test this hypothesis, the severity of renal fibrosis caused by unilateral ureteral obstruction (UUO) was compared in PAI-1 wild-type (+/+) and PAI-1 deficient (-/-) mice. The extent of interstitial inflammation and fibrosis, renal plasminogen activator and plasmin activity, and renal expression of profibrotic genes was evaluated after 3, 7, and 14 days of UUO.

Results: Renal PAI-1 mRNA levels increased 8- to 16-fold in the +/+ mice after UUO surgery, and PAI-1 protein was detected in kidney homogenates. Interstitial fibrosis was significantly attenuated in -/- mice compared with +/+ mice at day 7 and day 14, based on the interstitial area stained with picrosirius red and total kidney collagen content. However, neither the mean renal plasminogen activator nor plasmin activities were increased in -/- mice compared with +/+ mice. The number of interstitial macrophages were significantly lower in the -/- mice three and seven days after UUO; interstitial myofibroblasts were significantly fewer at three days. At the same time points, this altered interstitial cellularity was associated with a significant reduction in renal mRNA levels for transforming growth factor-beta and procollagens alpha 1(I) and alpha 1(III).

Conclusions: These studies establish an important fibrogenic role for PAI-1 in the renal fibrogenic response. The results demonstrate that one important fibrosis-promoting function of PAI-1 is its role in the recruitment of fibrosis-inducing cells, including myofibroblasts and macrophages.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chemotaxis, Leukocyte / physiology
  • Fibrinolysin / metabolism
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis
  • Kidney / immunology
  • Kidney / metabolism
  • Kidney / pathology
  • Macrophages / cytology
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nephritis, Interstitial / immunology
  • Nephritis, Interstitial / metabolism
  • Nephritis, Interstitial / pathology
  • Plasminogen Activator Inhibitor 1 / deficiency
  • Plasminogen Activator Inhibitor 1 / genetics*
  • Plasminogen Activators / metabolism
  • Ureteral Obstruction / immunology
  • Ureteral Obstruction / metabolism*
  • Ureteral Obstruction / pathology*

Substances

  • Plasminogen Activator Inhibitor 1
  • Plasminogen Activators
  • Fibrinolysin