Pioglitazone attenuates TGF-beta(1)-induction of fibronectin synthesis and its splicing variant in human mesangial cells via activation of peroxisome proliferator-activated receptor (PPAR)gamma.
The peroxisome proliferator-activated receptor (PPAR)gamma is expressed not only in adipose tissue but also in macrophages/monocytes and plays important roles in acute/chronic inflammation. Transforming growth factor (TGF)-beta is a common pathogenic indicator of sclerosis because it induces the accumulation of extracellular matrix (ECM) in the glomerular mesangium of the kidney. Among components of the ECM, fibronectin (FN) is an acute reactant in inflammation, and isoforms of it produced by splicing of gene variants appear during abnormal conditions such as wound healing. In this study, we examined the effects of pioglitazone, a PPARgamma agonist, on TGF-beta(1)-induced FN synthesis in cultured mesangial cells using RT-PCR and Western blot analysis. We also analyzed its splicing variant, extra domain (ED) A, containing FN (EDA(+)FN). TGF-beta(1) enhanced the production of both FN and EDA(+) FN and down-regulated PPARgamma expression. Pioglitazone reversed both these effects of TGF-beta(1). These findings suggest that PPARgamma activation by pioglitazone may affect the TGF-beta(1)-induced FN accumulation observed in the glomerular mesangium in cases of glomerulosclerosis, although further in vivo experiments are needed to evaluate this inference.
Maeda
Atsuko
A
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan.
Horikoshi
Satoshi
S
Gohda
Tomohito
T
Tsuge
Toshinao
T
Maeda
Kunimi
K
Tomino
Yasuhiko
Y
D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D005353:Fibronectins; D047495:PPAR gamma; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077205:Pioglitazone