Antifibrotic Effect by Activation of Peroxisome Proliferator-activated Receptor-gamma in Corneal Fibroblasts

Overview

Journal Mol Vis

Specialties Cell Biology
Molecular Biology
Ophthalmology

Date 2009 Nov 26

PMID 19936025

Citations 24

Authors

Hongwei Pan

Jiansu Chen

Jintang Xu

Miaojiao Chen

Rong Ma

Affiliations

Soon will be listed here.

Abstract

Purpose: The transformation of quiescent keratocytes to active phenotypes and the ensuing fibrotic response play important roles in corneal scar formation. This study aims to observe the antifibrotic effect of peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist on corneal fibroblasts cultured in vitro, and to explore the potential application of peroxisome proliferator-activated receptor agonist to the prevention of corneal opacity following wound repair.

Methods: Rabbit corneal keratocytes were cultured in a medium containing 10% serum to induce their transformation to fibroblasts and myofibroblasts, which are similar to those that repair corneas. After incubation with the PPARgamma agonist pioglitazone at different concentrations, the effect of pioglitazone on the migration, contractility, and viability of corneal fibroblasts was examined. The secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 was determined by gelatin zymography, and the synthesis of collagen I and fibronectin was investigated by western blotting.

Results: Treatment with pioglitazone at concentrations ranging from 1 to 10 mum significantly decreased corneal fibroblast migration, as determined by scrape-wound assay, inhibited corneal fibroblast-induced collagen lattice contraction, and reduced MMP-2 and MMP-9 secretion into the supernatant of cell cultures in a dose-dependent manner. The expression of fibronectin was significantly decreased, while the expression of collagen I was only decreased when treated with 10 mum pioglitazone. Cell viability was not evidently changed compared to the control.

Conclusion: This in vitro study demonstrated the anti-fibrotic effect of pioglitazone, suggesting that activation of PPARgamma may be a new approach for the treatment of corneal opacity and scar formation in the corneal wound healing process.

Citing Articles

Potential therapeutic effects of peroxisome proliferator-activated receptors on corneal diseases.

Chow B, Yu Lee I, Liu C, Liu Y Exp Biol Med (Maywood). 2024; 249:10142.

PMID: 38993197 PMC: 11238193. DOI: 10.3389/ebm.2024.10142.

Development and Validation of an HPLC-MS/MS Method for Pioglitazone from Nanocarriers Quantitation in Ex Vivo and In Vivo Ocular Tissues.

Miralles-Cardiel E, Silva-Abreu M, Calpena A, Casals I Pharmaceutics. 2021; 13(5).

PMID: 34063615 PMC: 8147631. DOI: 10.3390/pharmaceutics13050650.

The role of peroxisome proliferator-activated receptors in healthy and diseased eyes.

Escandon P, Vasini B, Whelchel A, Nicholas S, Matlock H, Ma J Exp Eye Res. 2021; 208:108617.

PMID: 34010603 PMC: 8594540. DOI: 10.1016/j.exer.2021.108617.

Corneal stromal wound healing: Major regulators and therapeutic targets.

Kamil S, Mohan R Ocul Surf. 2020; 19:290-306.

PMID: 33127599 PMC: 9183221. DOI: 10.1016/j.jtos.2020.10.006.

Anti-inflammatory and anti-proliferative action of adiponectin mediated by insulin signaling cascade in human vascular smooth muscle cells.

Cersosimo E, Xu X, Terasawa T, Dong L Mol Biol Rep. 2020; 47(9):6561-6572.

PMID: 32789574 DOI: 10.1007/s11033-020-05707-w.

References

Berger J, Akiyama T, Meinke P . PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci. 2005; 26(5):244-51. DOI: 10.1016/j.tips.2005.03.003. View

Zafiriou S, Stanners S, Saad S, Polhill T, Poronnik P, Pollock C . Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts. J Am Soc Nephrol. 2005; 16(3):638-45. DOI: 10.1681/ASN.2004040278. View

Yang L, Chan C, Kwon O, Liu S, McGhee J, Stimpson S . Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2006; 291(5):G902-11. DOI: 10.1152/ajpgi.00124.2006. View

Li Y, Wen X, Spataro B, Hu K, Dai C, Liu Y . hepatocyte growth factor is a downstream effector that mediates the antifibrotic action of peroxisome proliferator-activated receptor-gamma agonists. J Am Soc Nephrol. 2005; 17(1):54-65. PMC: 1820837. DOI: 10.1681/ASN.2005030257. View

Yamanaka O, Miyazaki K, Kitano A, Saika S, Nakajima Y, Ikeda K . Suppression of injury-induced conjunctiva scarring by peroxisome proliferator-activated receptor gamma gene transfer in mice. Invest Ophthalmol Vis Sci. 2008; 50(1):187-93. DOI: 10.1167/iovs.08-2282. View

Ye H, Maeda M, Yu F, Azar D . Differential expression of MT1-MMP (MMP-14) and collagenase III (MMP-13) genes in normal and wounded rat corneas. Invest Ophthalmol Vis Sci. 2000; 41(10):2894-9. View

West-Mays J, Sadow P, Tobin T, Strissel K, Cintron C, Fini M . Repair phenotype in corneal fibroblasts is controlled by an interleukin-1 alpha autocrine feedback loop. Invest Ophthalmol Vis Sci. 1997; 38(7):1367-79. View

Berryhill B, Kane B, Stramer B, Fini M, Hassell J . Increased SPARC accumulation during corneal repair. Exp Eye Res. 2003; 77(1):85-92. DOI: 10.1016/s0014-4835(03)00060-5. View

Wilson S, Cavanagh H, Petroll W, Jester J . Characterization of SV40-transfected cell strains from rabbit keratocytes. Cornea. 1997; 16(1):72-8. View

10.

Saika S, Yamanaka O, Okada Y, Miyamoto T, Kitano A, Flanders K . Effect of overexpression of PPARgamma on the healing process of corneal alkali burn in mice. Am J Physiol Cell Physiol. 2007; 293(1):C75-86. DOI: 10.1152/ajpcell.00332.2006. View

11.

Jester J, Huang J, Petroll W, Cavanagh H . TGFbeta induced myofibroblast differentiation of rabbit keratocytes requires synergistic TGFbeta, PDGF and integrin signaling. Exp Eye Res. 2002; 75(6):645-57. DOI: 10.1006/exer.2002.2066. View

12.

Netto M, Mohan R, Sinha S, Sharma A, Dupps W, Wilson S . Stromal haze, myofibroblasts, and surface irregularity after PRK. Exp Eye Res. 2005; 82(5):788-97. PMC: 2693937. DOI: 10.1016/j.exer.2005.09.021. View

13.

Evans R . The steroid and thyroid hormone receptor superfamily. Science. 1988; 240(4854):889-95. PMC: 6159881. DOI: 10.1126/science.3283939. View

14.

Jaster R, Lichte P, Fitzner B, Brock P, Glass A, Karopka T . Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells. J Cell Mol Med. 2005; 9(3):670-82. PMC: 6741639. DOI: 10.1111/j.1582-4934.2005.tb00497.x. View

15.

Kaji Y, Obata H, Usui T, Soya K, Machinami R, Tsuru T . Three-dimensional organization of collagen fibrils during corneal stromal wound healing after excimer laser keratectomy. J Cataract Refract Surg. 1998; 24(11):1441-6. DOI: 10.1016/s0886-3350(98)80164-8. View

16.

Hao G, Niu X, Gao D, Wei J, Wang N . Agonists at PPAR-gamma suppress angiotensin II-induced production of plasminogen activator inhibitor-1 and extracellular matrix in rat cardiac fibroblasts. Br J Pharmacol. 2008; 153(7):1409-19. PMC: 2437920. DOI: 10.1038/bjp.2008.21. View

17.

Blalock T, Duncan M, Varela J, Goldstein M, Tuli S, Grotendorst G . Connective tissue growth factor expression and action in human corneal fibroblast cultures and rat corneas after photorefractive keratectomy. Invest Ophthalmol Vis Sci. 2003; 44(5):1879-87. DOI: 10.1167/iovs.02-0860. View

18.

Nakamoto M, Ohya Y, Shinzato T, Mano R, Yamazato M, Sakima A . Pioglitazone, a thiazolidinedione derivative, attenuates left ventricular hypertrophy and fibrosis in salt-sensitive hypertension. Hypertens Res. 2008; 31(2):353-61. DOI: 10.1291/hypres.31.353. View

19.

Maltseva O, Folger P, Zekaria D, Petridou S, Masur S . Fibroblast growth factor reversal of the corneal myofibroblast phenotype. Invest Ophthalmol Vis Sci. 2001; 42(11):2490-5. View

20.

Cook J, Mody M, Fini M . Failure to activate transcription factor NF-kappaB in corneal stromal cells (keratocytes). Invest Ophthalmol Vis Sci. 1999; 40(13):3122-31. View