Positive Feedback Loop between Plasminogen Activator Inhibitor-1 and Transforming Growth Factor-Beta1 during Renal Fibrosis in Diabetes

Abstract

Background/Aims: Plasminogen activator inhibitor (PAI)-1 is increasingly recognized as a profibrotic factor but the mechanisms are not entirely clear. The present study examined the profibrotic mechanism of PAI-1 focusing on its effect on transforming growth factor (TGF)-β1 in experimental diabetes. Methods: PAI-1 knockout (KO) mesangial cells cultured under high glucose (HG) in addition to streptozotocin-induced diabetic PAI-1 KO mice were used. Results: PAI-1 deficiency did not affect plasma glucose significantly but reduced the fractional mesangial area, fibronectin and collagen I expression in the renal cortex after 20 weeks of diabetes as well as in HG-stimulated mesangial cells along with suppression of TGF-β1 mRNA expression. PAI-1 deficiency also reduced HG-induced βig-h3, a TGF-β1-induced gene product, mRNA expression. All these losses-of-function in PAI-1 KO mesangial cells were effectively gained by recombinant PAI-1. Recombinant PAI-1-induced fibronectin and collagen I expression was abrogated by TGF-β1 receptor inhibitor or anti-TGF-β antibody suggesting that the effect of PAI-1 was mediated by TGF-β1. In a similar context, recombinant PAI-1 stimulated TGF-β1 promoter activity to the same extent as TGF-β1 itself. Conclusion: Since TGF-β1 is well known to stimulate the PAI-1 promoter, we suggest that TGF-β1 and PAI-1 together constitute a positive feedback loop in the development of renal fibrosis in diabetes.

Honokiol ameliorates renal fibrosis by inhibiting extracellular matrix and pro‐inflammatory factors in vivo and in vitro

“…On the other hand, the ECM is normally continually degraded and accumulation of ECM may also result from a deficit in ECM degradation. The plasminogen activation system is one of the most important degrading systems for the ECM (Eddy et al, 2006;Fogo, 2003) and several studies have shown that synthesis and deposition of the inhibitory protein PAI-1 are increased in the kidney during experimental and human nephropathies (Rerolle et al, 2000;Eddy et al, 2006;Seo et al, 2009). PAI-1 is also one of the targets regulated by TGF-b1 (Keeton et al, 1991).…”

Plasminogen Activator Inhibitor-1 Antisense Oligodeoxynucleotides Abrogate Mesangial Fibronectin Accumulation

“…As discussed above, the increment of plasmin and MMP-2 activity may have played a role in decreased fibronectin accumulation. On the other hand, PAI-1 can activate profibrotic protein synthesis via the uPA receptor [14,16]. We have also observed that recombinant PAI-1 stimulates TGF-β1 promoter activity and induces fibronectin and collagen I expression in mouse mesangial cells [16].…”

“…On the other hand, PAI-1 can activate profibrotic protein synthesis via the uPA receptor [14,16]. We have also observed that recombinant PAI-1 stimulates TGF-β1 promoter activity and induces fibronectin and collagen I expression in mouse mesangial cells [16]. It is possible that PAI-1 antisense ODN-mediated fibronectin protein may be mediated by active suppression of ECM synthesis.…”

“…In the normal human kidney, PAI-1 is undetectable in the basal level but the expression is upregulated in several acute and chronic kidney diseases [9,10] including diabetic nephropathy [11]. A functional role of PAI-1 in renal diseases was established mainly by in vivo studies using PAI-1 knock out (KO) mice; renal fibrosis in crescentic glomerulonephritis [12], unilateral ureteral obstruction [13], and diabetic nephropathy [14][15][16] was attenuated in PAI-1 KO mice. In addition, mutant, non-inhibitory human PAI-1 peptide decreased proteinuria as well as fibrosis in experimental renal injury models [17][18][19].…”

Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

“…Suppression of PAI-1 by siRNA protects affected mice from the development and progression of pulmonary fibrosis (Senoo, Hattori et al 2010). A positive feedback loop between TGF-β and PAI-1 is involved in the development of renal fibrosis in diabetes (Seo, Park et al 2009). TGF-β induces fibronectin and collagen I expression through PAI-1, at the same time PAI-1 activates transcription of TGF-β in mouse mesangial cells (Seo, Park et al 2009).…”