[HTML][HTML] PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction

T Oda, YO Jung, HS Kim, X Cai, JM López-Guisa… - Kidney international, 2001 - Elsevier
T Oda, YO Jung, HS Kim, X Cai, JM López-Guisa, Y Ikeda, AA Eddy
Kidney international, 2001Elsevier
PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction. 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 …
PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction.
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-β and procollagens α1(I) and α1(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.
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