Hepatocyte Growth Factor Is a Downstream Effector that Mediates the Antifibrotic Action of Peroxisome Proliferator-Activated Receptor- Agonists

Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 02/2006; 17(1):54-65. DOI: 10.1681/ASN.2005030257
Source: PubMed


Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-dependent transcription factor that plays an important role in the regulation of insulin sensitivity and lipid metabolism. Evidence shows that PPAR-γ agonists also ameliorate renal fibrotic lesions in both diabetic nephropathy and nondiabetic chronic kidney disease. However, little is known about the mechanism underlying their antifibrotic action. This study demonstrated that PPAR-γ agonists could exert their actions by inducing antifibrotic hepatocyte growth factor (HGF) expression. Incubation of mesangial cells with natural or synthetic PPAR-γ agonists 15-deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2) or troglitazone and ciglitazone suppressed TGF-β1-mediated α-smooth muscle actin, fibronectin, and plasminogen activator inhibitor-1 expression. PPAR-γ agonists also induced HGF mRNA expression and protein secretion. Transfection studies revealed that 15d-PGJ2 stimulated HGF gene promoter activity, which was dependent on the presence of a novel peroxisome proliferator response element. Treatment of mesangial cells with 15d-PGJ2 induced the binding of PPAR-γ to the peroxisome proliferator response element in the HGF promoter region. PPAR-γ agonists also activated c-met receptor tyrosine phosphorylation, induced Smad transcriptional co-repressor TG-interacting factor expression, and blocked TGF-β/Smad-mediated gene transcription in mesangial cells. Furthermore, ablation of c-met receptor through the LoxP-Cre system in mesangial cells abolished the antifibrotic effect of 15d-PGJ2. PPAR-γ activation also induced HGF expression in renal interstitial fibroblasts and repressed TGF-β1-mediated myofibroblast activation. Both HGF and 15d-PGJ2 attenuated Smad nuclear translocation in response to TGF-β1 stimulation in renal fibroblasts. Together, these findings suggest that HGF may act as a downstream effector that mediates the antifibrotic action of PPAR-γ agonists.

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Available from: Xiaoyan Wen, Jul 25, 2014
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    • "In mesangial cells, PPAR ligands (15d-PGJ2, troglitazone , and ciglitazone) stimulated the expression of hepatocyte growth factor (HGF), an endogenous antifibrotic agent. HGF induces the Smad transcriptional corepressor TG-interacting factor (TGIF) thus mediating autocrine suppression of TGF--induced fibrogenic responses [44] [45]. Contrary to the mentioned findings, some studies suggested that antifibrotic effects of PPAR ligands could not be related to PPAR activation [46] [47] [48] [49]. "
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    ABSTRACT: Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPAR ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPAR function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPAR as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis.
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    • "In contrast to diabetic nephropathy, much less is known about the effects of PPARγ agonists in non-diabetic nephropathies . There have been reports of thiazolidinediones attenuating progression of renal damage without primary metabolic disturbance, including those associated with renal mass reduction (Ma et al., 2001), nephrotoxic nephrotoxic (Liu et al., 2010; Yang et al., 2006; Zhou et al., 2012) and immune injury (Benigni et al., 2006), suggesting the general renoprotective properties of PPARγ agonists might be independent of their systemic metabolic effects. Adriamycin-induced nephropathy represents a well-established, normotensive, normoglycemic model of chronic renal damage (Okuda et al., 1986). "
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    ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to ameliorate diabetic nephropathy, but much less is known about their effects in non-diabetic nephropathies. In the present study, metabolic parameters, blood pressure, aortic endothelial function along with molecular and structural markers of glomerular and tubulointerstitial renal damage, were studied in a rat model of normotensive nephropathy induced by adriamycin and treated with PPARγ agonist pioglitazone (12mg/kg, po), angiotensin converting enzyme (ACE) inhibitor ramipril (1mg/kg, po) or their combination. Pioglitazone had no effect on systolic blood pressure, marginally reduced glycemia and improved aortic endothelium-dependent relaxation. In the kidney, pioglitazone prevented the development of proteinuria and focal glomerulosclerosis to the similar extent as blood-pressure lowering ramipril. Renoprotection provided by either treatment was associated with a reduction in the cortical expression of profibrotic plasminogen activator inhibitor-1 and microvascular damage-inducing endothelin-1, and a limitation of interstitial macrophage influx. Treatment with PPARγ agonist, as well as ACE inhibitor comparably affected renal expression of renin-angiotensin system (RAS) components, normalizing increased renal expression of ACE and enhancing the expression of Mas receptor. Interestingly, combined pioglitazone and ramipril treatment did not provide any additional renoprotection. These results demonstrate that in a nondiabetic renal disease, such as adriamycin-induced nephropathy, PPARγ agonist pioglitazone provides renoprotection to a similar extent as an ACE inhibitor by interfering with the expression of local RAS components and attenuating related profibrotic and inflammatory mechanisms. The combination of the both agents, however, does not lead to any additional renal benefit.
    Full-text · Article · Feb 2014 · European journal of pharmacology
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    • "It has been described that HGF can interfere with SMAD-mediated signaling at different levels. Thus, HGF can negatively regulate SMAD nuclear translocation [48], [49] and SMAD-dependent transcriptional activity by increasing the expression of the SMAD co-repressor SnoN [50]. Therefore, it was plausible that autocrine HGF signaling in Metflx/flx oval cells may impair or modulate TGF-β signaling leading to an impairment of TGF-β-mediated apoptosis. "
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    ABSTRACT: We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met(-/-) oval cells) are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met (Met(flx/flx)), demonstrating that the HGF/Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Met(flx/flx) and Met(-/-) oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met(-/-) oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4) mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met(-/-) oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Met(flx/flx) oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met(-/-) oval cells. Interestingly, both PI3K inhibition and/or knockdown itself resulted in caspase-3 activation and loss of viability in Met(flx/flx) oval cells, whereas no effect was observed in Met(-/-) oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF/Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis.
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