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

Oda T, Jung YO, Kim HS, Cai X, López-Guisa JM, Ikeda Y, Eddy AA
Kidney Int. 2001 60 (2): 587-96

PMID: 11473641 · DOI:10.1046/j.1523-1755.2001.030002587.x

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.

MeSH Terms (15)

Animals Chemotaxis, Leukocyte Fibrinolysin Fibroblasts Fibrosis Kidney Macrophages Male Mice Mice, Inbred C57BL Mice, Knockout Nephritis, Interstitial Plasminogen Activator Inhibitor 1 Plasminogen Activators Ureteral Obstruction

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