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Positive feedback loop between plasminogen activator inhibitor-1 and transforming growth factor-beta1 during renal fibrosis in diabetes

Title
Positive feedback loop between plasminogen activator inhibitor-1 and transforming growth factor-beta1 during renal fibrosis in diabetes
Authors
Seo J.Y.Park J.Yu M.R.Kim Y.S.Ha H.Lee H.B.
Ewha Authors
하헌주
SCOPUS Author ID
하헌주scopus
Issue Date
2009
Journal Title
American Journal of Nephrology
ISSN
0250-8095JCR Link
Citation
vol. 30, no. 6, pp. 481 - 490
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. Copyright © 2009 S. Karger AG, Basel.
DOI
10.1159/000242477
Appears in Collections:
약학대학 > 약학과 > Journal papers
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