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


CONCLUSIONS
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.
Seo
Ji Yeon
JY
Department of Bioinspired Science, Division of Life and Pharmaceutical Sciences, and College of Pharmacy, Ewha Womans University, Seoul, Korea.
Park
Jehyun
J
Yu
Mi Ra
MR
Kim
Yu Seun
YS
Ha
Hunjoo
H
Lee
Hi Bahl
HB
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D025461:Feedback, Physiological / Q000502:physiology*; D005341:Fibrinolysin / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009997:Osmotic Pressure / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D058258:Serpin E2; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D024042:Collagen Type I; D024141:Collagen Type IV; D005353:Fibronectins; D012333:RNA, Messenger; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D053773:Transforming Growth Factor beta1; D005341:Fibrinolysin; D020780:Matrix Metalloproteinase 9