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

@article{citeulike:6091325, 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)-beta1 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-beta1 mRNA expression. PAI-1 deficiency also reduced HG-induced betaig-h3, a TGF-beta1-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-beta1 receptor inhibitor or anti-TGF-beta antibody suggesting that the effect of PAI-1 was mediated by TGF-beta1. In a similar context, recombinant PAI-1 stimulated TGF-beta1 promoter activity to the same extent as TGF-beta1 itself. Conclusion: Since TGF-beta1 is well known to stimulate the PAI-1 promoter, we suggest that TGF-beta1 and PAI-1 together constitute a positive feedback loop in the development of renal fibrosis in diabetes.}, author = {Seo, Ji Yeon Y. and Park, Jehyun and Yu, Mi Ra R. and Kim, Yu Seun S. and Ha, Hunjoo and Lee, Hi Bahl B.}, citeulike-article-id = {6091325}, citeulike-linkout-0 = {http://dx.doi.org/10.1159/000242477}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19786738}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19786738}, day = {25}, doi = {10.1159/000242477}, issn = {1421-9670}, journal = {American journal of nephrology}, keywords = {dn, mc, pai1, tgfb}, month = {September}, number = {6}, pages = {481--490}, posted-at = {2009-11-10 04:35:27}, priority = {2}, title = {Positive Feedback Loop between Plasminogen Activator Inhibitor-1 and Transforming Growth Factor-Beta1 during Renal Fibrosis in Diabetes.}, url = {http://dx.doi.org/10.1159/000242477}, volume = {30}, year = {2009} }

TY - JOUR ID - citeulike:6091325 L3 - citeulike-article-id:6091325 N2 - 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)-beta1 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-beta1 mRNA expression. PAI-1 deficiency also reduced HG-induced betaig-h3, a TGF-beta1-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-beta1 receptor inhibitor or anti-TGF-beta antibody suggesting that the effect of PAI-1 was mediated by TGF-beta1. In a similar context, recombinant PAI-1 stimulated TGF-beta1 promoter activity to the same extent as TGF-beta1 itself. Conclusion: Since TGF-beta1 is well known to stimulate the PAI-1 promoter, we suggest that TGF-beta1 and PAI-1 together constitute a positive feedback loop in the development of renal fibrosis in diabetes. IS - 6 JF - American journal of nephrology SN - 1421-9670 EP - 490 TI - Positive Feedback Loop between Plasminogen Activator Inhibitor-1 and Transforming Growth Factor-Beta1 during Renal Fibrosis in Diabetes. VL - 30 SP - 481 KW - dn KW - mc KW - pai1 KW - tgfb AU - Seo, Ji Yeon AU - Park, Jehyun AU - Yu, Mi Ra AU - Kim, Yu Seun AU - Ha, Hunjoo AU - Lee, Hi Bahl PY - 2009/09/25/ UR - http://dx.doi.org/10.1159/000242477 ER -