PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction.

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.

• Authors: T Oda, Y O Jung, H S Kim, X Cai, J M López-Guisa, Y Ikeda, A A Eddy
• Journal: Kidney international (Kidney Int) Vol. 60 Issue 2 Pg. 587-96 (Aug 2001) ISSN: 0085-2538 [Print] United States
• PMID: 11473641 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Plasminogen Activator Inhibitor 1
• Plasminogen Activators
• Fibrinolysin

Topics

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