Pioglitazone inhibits TGFβ induced keratocyte transformation to myofibroblast and extracellular matrix production.
Phenotype transformation of corneal keratocyte to myofibroblast plays an important role in the wound healing process of cornea and TGFβ is considered to be the most important mediator to induce myofibroblast trans-differentiation. Peroxisome proliferator-activated receptors-γ (PPAR-γ) activation has been proved to exert anti-fibrotic effect in many tissues. In this study, we investigated the effect of PPAR-γ agonist, pioglitazone, on myofibroblast transformation, extracellular matrix production and cell proliferation. The results showed pioglitazone inhibited the TGFβ-driven myofibroblast differentiation, as determined by F-actin fluorescence staining, α-smooth muscle actin-specific immunocytochemistry and western blot analysis. Pioglitazone also potently attenuated TGFβ induced type I collagen and fibronectin mRNA and protein production. Moreover, pioglitazone showed inhibitory effect on TGFβ induced cell proliferation. The irreversible PPAR-γ antagonist GW9662, partially reversed the inhibition of collagen I and fibronectin expression but not myofibroblast transformation, suggesting both PPAR-γ dependent and PPAR-γ independent mechanisms were involved in the action of pioglitazone. Therefore, our study indicates pioglitazone has a potential application in therapy of corneal fibrosis and PPAR-γ might be a promising therapy target.
Department of Ophthalmology, Medical College, Jinan University, West Huangpu Avenue 601, Guangzhou 510632, China. panhongwei@hotmail.com
Hong-Wei
HW
Pan
Jin-Tang
JT
Xu
Jian-Su
JS
Chen
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D060527:Corneal Keratocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058628:Myofibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000199:Actins; D024042:Collagen Type I; D005353:Fibronectins; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077205:Pioglitazone