Rosiglitazone attenuates activation of human Tenon’s fibroblasts induced by transforming growth factor -β1

Fan, Fang; Li, Yuehua; Duan, Xuanchu; Zhao, Tantai; Pan, Dongning; Chen, Huihui

doi:10.1007/s00417-011-1903-6

Cited by 10 publications

(14 citation statements)

References 23 publications

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“…Rosiglitazone is known for its ability to improve insulin sensitivity and has been used extensively in patients with non-insulin-dependent diabetes mellitus. However, rosiglitazone has been proven to have an anti-fibrotic effect in multiple organs [24]–[26], and we previously demonstrated that rosiglitazone exerts its anti-fibrotic effect through suppression of Smad2/3 [12]. In this study, we investigated the effect of rosiglitazone on the p38 signaling pathway.…”

Section: Discussionmentioning

confidence: 96%

“…Human Tenon fibroblasts were seeded in six-well plates, and scratch wounds were induced as described previously [12]. After suspended particles were washed away, we pretreated the cells with rosiglitazone for 2 h or SB203580 for 1 h in serum-starved medium.…”

Section: Methodsmentioning

confidence: 99%

“…Peroxisome proliferator–activated receptor-γ (PPAR-γ), which belongs to nuclear hormone receptor superfamily of ligand-activated transcription factors, has been found to regulate fibrosis in multiple organs [10], [11]. Our previous study demonstrated that rosiglitazone, a synthetic PPAR-γ agonist, could moderately antagonize TGF-β1–induced fibrosis by interfering TGF-β/Smad pathway in vitro [12]. However, the mechanism of p38 pathway involvement in fibrosis after filtration surgery has not been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

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Rosiglitazone Inhibits TGF-β 1 Induced Activation of Human Tenon Fibroblasts via p38 Signal Pathway

et al. 2014

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PurposeTransdifferentiation of human Tenon fibroblasts to myofibroblasts and subsequent deposition of extracellular matrix is a key step in the scarring after glaucoma filtration surgery. The p38 signaling pathway plays an important role in cell proliferation and differentiation, and its upstream regulators and downstream molecules are widely distributed in the eye. We aimed to investigate the role of p38 in the activation of Tenon fibroblasts and that of the anti-fibrotic mechanism of rosiglitazone in the modulation of the p38 signaling pathway.MethodsCultured Tenon fibroblasts were stimulated with transforming growth factor (TGF)-β1. Activation of p38 was examined by western blot analysis. Rosiglitazone and blocking of the p38 signaling pathway by SB203580 were used to antagonize stimulation by TGF-β1. Fibroblast motility was examined by wound closure assay; alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were determined by qPCR and western blot. Expression and localization of alpha-smooth muscle actin were determined by immunofluorescence staining.ResultsPhosphorylated p38 was upregulated in fibroblasts stimulated with TGF-β1, and this effect was substantially inhibited by rosiglitazone. Proliferation and migration of fibroblasts were suppressed by rosiglitazone and SB203580. Expression of alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were decreased at the mRNA and protein levels by rosiglitazone and SB203580. However, the inhibitory effect of SB203580 on transcription and protein expression was weaker than that of rosiglitazone. Similar phenomena were found on immunofluorescence microscopy of alpha-smooth muscle actin.ConclusionsThe p38 signaling pathway mediates the TGF-β1-induced transdifferentiation of human Tenon fibroblasts to myofibroblasts. Rosiglitazone can exert anti-fibrotic activity by interfering with the TGF-β/p38 signaling pathway and might be useful for modulating scar formation after glaucoma filtration surgery.

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Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rosiglitazone Inhibits TGF-β 1 Induced Activation of Human Tenon Fibroblasts via p38 Signal Pathway

et al. 2014

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“…troglitazone, rosiglitazone, and pioglitazone) have anti-fibrogenic effect in several body tissues, including the lungs, skin, kidneys, eyes and heart [26–35]. The PPAR-γ agonists inhibit fibrogenesis by regulating the Smad-dependent [27, 30–33] or Smad-independent [23, 29, 31, 36] TGF-β signaling pathways. The mechanism of anti-fibrotic action of PPAR-γ agonists is under investigation but involves both PPAR-γ dependent [26, 32, 37, 38] and PPAR-γ independent [28, 31, 34–36] pathways.…”

Section: Introductionmentioning

confidence: 99%

Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts

et al. 2017

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BackgroundIntestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn’s disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- γ (PPAR-γ) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-γ agonists on human primary intestinal myofibroblasts (HIFs).MethodsHIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-β1 and co-incubated with or without one of two synthetic PPAR-γ agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and α-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-β1 induced expression of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs. The irreversible PPAR-γ antagonist GW9662 was used to investigate whether the effect of PPAR-γ agonists was PPAR-γ dependent.ResultsBoth PPAR-γ agonists reduced the TGF-β1-induced expression of α-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and α-smooth muscle actin-specific immunocytochemistry. PPAR-γ agonists also inhibited TGF-β1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and α-smooth muscle actin. TGF-β1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-β1 induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-γ agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-γ independent.ConclusionsTroglitazone and rosiglitazone suppress TGF-β1-induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-017-0627-4) contains supplementary material, which is available to authorized users.

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“…It may also suppress invasion of macrophages into the healing subconjunctival tissue and generation of myofibroblasts [51]. Consistent with this result, Fan [52] and his fellows reported that rosiglitazone can effectively attenuate activation of human Tenon's fibroblasts (HTFs) induced by TGF β 1 without obvious toxicity. The possible mechanism might be that rosiglitazone interferes with TGF β /Smad signaling pathway.…”

Section: Ppar γ and Ocular Diseasementioning

confidence: 82%

Role of Peroxisome Proliferator-Activated Receptorγin Ocular Diseases

Zhang

2015

Journal of Ophthalmology

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Peroxisome proliferator-activated receptor γ (PPAR γ), a member of the nuclear receptor superfamily, is a ligand-activated transcription factor that plays an important role in the control of a variety of physiological processes. The last decade has witnessed an increasing interest for the role played by the agonists of PPAR γ in antiangiogenesis, antifibrosis, anti-inflammation effects and in controlling oxidative stress response in various organs. As the pathologic mechanisms of major blinding diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), keratitis, and optic neuropathy, often involve neoangiogenesis and inflammation- and oxidative stress-mediated cell death, evidences are accumulating on the potential benefits of PPAR γ to improve or prevent these vision threatening eye diseases. In this paper we describe what is known about the role of PPAR γ in the ocular pathophysiological processes and PPAR γ agonists as novel adjuvants in the treatment of eye diseases.

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Rosiglitazone attenuates activation of human Tenon’s fibroblasts induced by transforming growth factor -β1

Abstract: Rosiglitazone can effectively attenuate activation of HTFs induced by TGF-β1 without obvious toxicity. The possible mechanism might be that rosiglitazone interferes with TGF-β/Smad signaling pathway.

Cited by 10 publications

References 23 publications

Rosiglitazone Inhibits TGF-β 1 Induced Activation of Human Tenon Fibroblasts via p38 Signal Pathway

Rosiglitazone Inhibits TGF-β 1 Induced Activation of Human Tenon Fibroblasts via p38 Signal Pathway

Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts

Role of Peroxisome Proliferator-Activated Receptorγin Ocular Diseases

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