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PPAR-gamma agonists inhibit TGF-beta1-induced chemokine expression in human tubular epithelial cells.

ABSTRACT: AIM: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has a wide range of biological functions, including anti-inflammation. In this study, we investigated the inhibitory effects of PPAR-gamma on transforming growth factor beta1 (TGF-beta1)-induced interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) expression in renal tubular epithelial cells (HK-2). METHODS: HK-2 cells were pretreated with 15d-PGJ2 or troglitazone (TGL) and then treated with TGF-beta1. Expression of MCP-1 and IL-8 was measured using real-time PCR and ELISA. RESULTS: Treatment with 5 ng/mL TGF-beta1 for 24 h increased both MCP-1 and IL-8 mRNA and protein levels in HK-2 cells. Both 15d-PGJ2 at 2.5 and 5 micromol/L and TGL at 2.5 micromol/L exhibited inhibitory effects on TGF-beta1-induced MCP-1 expression. Additionally, 15d-PGJ2 at 2.5 and 5 micromol/L and TGL at 2.5 micromol/L inhibited TGF-beta1-induced expression of IL-8. CONCLUSION: PPAR-gamma agonists (15d-PGJ2 and TGL) could inhibit the TGF-beta1-induced expression of chemokines in HK-2 cells. Our results suggest that PPAR-gamma agonists have the potential to be used as a treatment regimen to reduce inflammation in renal tubulointerstitial disease.

PROVIDER: S-EPMC4006532 | BioStudies | 2009-01-01

REPOSITORIES: biostudies

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Project description:<h4>Background and purpose</h4>Peroxisome proliferator-activated receptor (PPAR)-gamma ligands have been shown to inhibit cardiac fibrosis. However, the underlying mechanisms are poorly understood. We investigated the regulation by PPAR-gamma ligands of angiotensin (Ang) II-induced plasminogen activator inhibitor (PAI)-1, extracellular matrix (ECM) production and cell growth in cardiac fibroblasts.<h4>Experimental approach</h4>The effects of PPAR-gamma ligands on Ang II-induced PAI-1, ECM expression and cell growth were assessed in primary-cultured rat cardiac fibroblasts; cardiac PAI-1 and ECM production was examined in Ang II-infused rats.<h4>Key results</h4>In growth-arrested cardiac fibroblasts, PPAR-gamma ligands rosiglitazone and 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) dose-dependently attenuated Ang II-induced cell proliferation and expression of PAI-1, collagen type-I, collagen type-III and fibronectin. An accompanying increase in PPAR-gamma expression and activation was also observed. These suppressive effects were attenuated by the PPAR-gamma antagonists GW9662 and bisphenol A diglycidyl ether (BADGE). Moreover, rosiglitazone and 15d-PGJ2 inhibited in part the expression and phosphorylation of Ang II-induced transforming growth factor (TGF)-beta1, Smad2/3 and c-Jun NH(2)-terminal kinase (JNK). Ang II infusion in rats markedly increased left ventricular production of PAI-1, collagen and fibronectin, with a concurrent increase in the ratios of heart weight/body weight and left ventricle weight/body weight. Co-treatment with rosiglitazone significantly decreased these levels and upregulated PPAR-gamma expression.<h4>Conclusions and implications</h4>Rosiglitazone and 15d-PGJ2 suppress Ang II-induced production of PAI-1 and ECM probably via interactions between PPAR-gamma and TGF-beta1/Smad2/3 and JNK signalling pathways. It is suggested that PPAR-gamma and its ligands may have potential applications in preventing cardiac fibrosis.

Project description:BACKGROUND: Circadian rhythms are endogenous, self-sustained oscillations with approximately 24-hr rhythmicity that are manifested in various physiological and metabolic processes. The circadian organization of these processes in mammals is governed by the master oscillator within the suprachiasmatic nuclei (SCN) of the hypothalamus. Recent findings revealed that circadian oscillators exist in most organs, tissues, and even in immortalized cells, and that the oscillators in peripheral tissues are likely to be coordinated by SCN, the master oscillator. Some candidates for endogenous entrainment factors have sporadically been reported, however, their details remain mainly obscure. RESULTS: We developed the in vitro real-time oscillation monitoring system (IV-ROMS) by measuring the activity of luciferase coupled to the oscillatory gene promoter using photomultiplier tubes and applied this system to screen and identify factors able to influence circadian rhythmicity. Using this IV-ROMS as the primary screening of entrainment factors for circadian clocks, we identified 12 candidates as the potential entrainment factor in a total of 299 peptides and bioactive lipids. Among them, four candidates (endothelin-1, all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid) have already been reported as the entrainment factors in vivo and in vitro. We demonstrated that one of the novel candidates, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), triggers the rhythmic expression of endogenous clock genes in NIH3T3 cells. Furthermore, we showed that 15d-PGJ2 transiently induces Cry1, Cry2, and Roralpha mRNA expressions and that 15d-PGJ2-induced entrainment signaling pathway is PPAR-gamma--and MAPKs (ERK, JNK, p38MAPK)-independent. CONCLUSION: Here, we identified 15d-PGJ2 as an entrainment factor in vitro. Using our developed IV-ROMS to screen 299 compounds, we found eight novel and four known molecules to be potential entrainment factors for circadian clocks, indicating that this assay system is a powerful and useful tool in initial screenings.

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PPAR-gamma agonists inhibit TGF-beta1-induced chemokine expression in human tubular epithelial cells.

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