Transforming Growth Factor-β and Long Non-coding RNA in Renal Inflammation and Fibrosis.
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ABSTRACT:
SUBMITTER: Gu YY
PROVIDER: S-EPMC8155637 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.
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Project description:Although long non-coding RNAs (lncRNAs) are important players in the initiation and progression of many pathological processes, the role of lncRNAs in renal fibrosis still remains unclear. We showed that lncRNA-H19 expression was significantly up-regulated in TGF-?2-induced HK-2 cell fibrosis and unilateral ureteral obstruction (UUO)-induced renal fibrosis in vivo. H19 knockdown significantly attenuated renal fibrosis in vitro and in vivo. LncRNA-H19, miR-17, and fibronectin constituted to a regulatory network involved in renal fibrosis. We also detected up-regulated H19 expression and down-regulated miR-17 expression in the early and advanced animal models of renal fibrosis. This study indicates that H19 up-regulation contributes to renal fibrosis. H19 inhibition might represent a novel anti-fibrotic treatment in renal diseases.
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Project description:One of the key characteristics of idiopathic pulmonary fibrosis (IPF) is accumulation of excess fibrous tissue in the lung, which leads to hypoxic conditions. Transforming growth factor (TGF) ? is a major mediator that promotes the differentiation of fibroblasts to myofibroblasts. However, how hypoxia and TGF? together contribute the pathogenesis of IPF is poorly understood. Long non-coding RNAs (lncRNAs) have regulatory effects on certain genes and are involved in many diseases. In this study, we determined the effects of hypoxia and/or TGF? on mRNA and lncRNA transcriptomes in pulmonary fibroblasts. Hypoxia and TGF?1 synergistically increased myofibroblast marker expression. RNA sequencing revealed that hypoxia and TGF?1 treatment resulted in significant changes in 669 lncRNAs and 2,676 mRNAs compared to 150 lncRNAs and 858 mRNAs in TGF?1 alone group and 222 lncRNAs and 785 mRNAs in hypoxia alone group. TGF?1 induced the protein expression of HIF-1?, but not HIF-2?. On the other hand, hypoxia enhanced the TGF?1-induced phosphorylation of Smad3, suggesting a cross-talk between these two signaling pathways. In all, 10 selected lncRNAs (five-up and five-down) in RNA sequencing data were validated using real-time PCR. Two lncRNAs were primarily located in cytoplasm, three in nuclei and five in both nuclei and cytoplasm. The silencing of HIF-1? and Smad3, but not Smad2 and HIF-2? rescued the downregulation of FENDRR by hypoxia and TGF?1. In conclusion, hypoxia and TGF?1 synergistically regulate mRNAs and lncRNAs involved in several cellular processes, which may contribute to the pathogenesis of IPF.
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Project description:Tissue remodeling/fibrosis is a major feature of all fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). It is underpinned by accumulating extracellular matrix (ECM) proteins. Fibulin-1c (Fbln1c) is a matricellular ECM protein associated with lung fibrosis in both humans and mice, and stabilizes collagen formation. Here we discovered that Fbln1c was increased in the lung tissues of IPF patients and experimental bleomycin-induced pulmonary fibrosis. Fbln1c-deficient (-/-) mice had reduced pulmonary remodeling/fibrosis and improved lung function after bleomycin challenge. Fbln1c interacted with fibronectin, periostin and tenascin-c in collagen deposits following bleomycin challenge. In a novel mechanism of fibrosis Fbln1c bound to latent transforming growth factor (TGF)-β binding protein-1 (LTBP1) to induce TGF-β activation, and mediated downstream Smad3 phosphorylation/signaling. This process increased myofibroblast numbers and collagen deposition. Fbln1 and LTBP1 co-localized in lung tissues from IPF patients. Thus, Fbln1c may be a novel driver of TGF-β-induced fibrosis involving LTBP1 and may be an upstream therapeutic target.
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Project description:Objective:SSc is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. IL-6 and related cytokines that signal through STAT3 have been implicated in the pathogenesis of SSc and mouse models of fibrosis. The aim of this study was to investigate the efficacy of inhibiting STAT3 in the development of fibrosis in two mouse models of skin fibrosis. Methods:Biopsy samples of skin from SSc patients and healthy control subjects were used to determine the expression pattern of phosphotyrosyl (pY705)-STAT3. C188-9, a small molecule inhibitor of STAT3, was used to treat fibrosis in the bleomycin-induced fibrosis model and Tsk-1 mice. In vitro studies were performed to determine the extent to which STAT3 regulates the fibrotic phenotype of dermal fibroblasts. Results:Increased STAT3 and pY705-STAT3 was observed in SSc skin biopsies and in both mouse models of SSc. STAT3 inhibition with C188-9 resulted in attenuated skin fibrosis, myofibroblast accumulation, pro-fibrotic gene expression and collagen deposition in both mouse models of skin fibrosis. C188-9 decreased in vitro dermal fibroblast production of fibrotic genes induced by IL-6 trans-signalling and TGF-β. Finally, TGF-β induced phosphotyrosylation of STAT3 in a SMAD3-dependent manner. Conclusion:STAT3 inhibition decreases dermal fibrosis in two models of SSc. STAT3 regulates dermal fibroblasts function in vitro and can be activated by TGF-β. These data suggest that STAT3 is a potential therapeutic target for dermal fibrosis in diseases such as SSc.
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Project description:PurposeTo study the role of long non-coding RNA (lncRNA) MALAT1 in transforming growth factor beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells.MethodsARPE-19 cells were cultured and exposed to TGF-β1. The EMT of APRE-19 cells is confirmed by morphological change, as well as the increased expression of alpha-smooth muscle actin (αSMA) and fibronectin, and the down-regulation of E-cadherin and Zona occludin-1(ZO-1) at both mRNA and protein levels. The expression of lncRNA MALAT1 in RPE cells were detected by quantitative real-time PCR. Knockdown of MALAT1 was achieved by transfecting a small interfering RNA (SiRNA). The effect of inhibition of MALAT1 on EMT, migration, proliferation, and TGFβ signalings were observed. MALAT1 expression was also detected in primary RPE cells incubated with proliferative vitreoretinopathy (PVR) vitreous samples.ResultsThe expression of MALAT1 is significantly increased in RPE cells incubated with TGFβ1. MALAT1 silencing attenuates TGFβ1-induced EMT, migration, and proliferation of RPE cells, at least partially through activating Smad2/3 signaling. MALAT1 is also significantly increased in primary RPE cells incubated with PVR vitreous samples.ConclusionLncRNA MALAT1 is involved in TGFβ1-induced EMT of human RPE cells and provides new understandings for the pathogenesis of PVR.
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Project description:Although transforming growth factor beta (TGF-β) is known to be involved in the pathogenesis and progression of many cancers, its role in renal cancer has not been fully investigated. In the present study, we examined the role of TGF-β in clear cell renal carcinoma (ccRCC) progression in vitro and in vivo. First, expression levels of TGF-β signaling pathway components were examined. Microarray and immunohistochemical analyses showed that the expression of c-Ski, a transcriptional corepressor of Smad-dependent TGF-β and bone morphogenetic protein (BMP) signaling, was higher in ccRCC tissues than in normal renal tissues. Next, a functional analysis of c-Ski effects was carried out. Bioluminescence imaging of renal orthotopic tumor models demonstrated that overexpression of c-Ski in human ccRCC cells promoted in vivo tumor formation. Enhancement of tumor formation was also reproduced by the introduction of a dominant-negative mutant TGF-β type II receptor into ccRCC cells. In contrast, introduction of the BMP signaling inhibitor Noggin failed to accelerate tumor formation, suggesting that the tumor-promoting effect of c-Ski depends on the inhibition of TGF-β signaling rather than of BMP signaling. Finally, the molecular mechanism of the tumor-suppressive role of TGF-β was assessed. Although TGF-β signaling did not affect tumor angiogenesis, apoptosis of ccRCC cells was induced by TGF-β. Taken together, these findings suggest that c-Ski suppresses TGF-β signaling in ccRCC cells, which, in turn, attenuates the tumor-suppressive effect of TGF-β.
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Project description:Intrahepatic cholangiocarcinoma (iCCA) is a deadly liver primary cancer associated with poor prognosis and limited therapeutic opportunities. Active transforming growth factor beta (TGF?) signaling is a hallmark of the iCCA microenvironment. However, the impact of TGF? on the transcriptome of iCCA tumor cells has been poorly investigated. Here, we have identified a specific TGF? signature of genes commonly deregulated in iCCA cell lines, namely HuCCT1 and Huh28. Novel coding and noncoding TGF? targets were identified, including a TGF?-induced long noncoding RNA (TLINC), formerly known as cancer susceptibility candidate 15 (CASC15). TLINC is a general target induced by TGF? in hepatic and nonhepatic cell types. In iCCA cell lines, the expression of a long and short TLINC isoform was associated with an epithelial or mesenchymal phenotype, respectively. Both isoforms were detected in the nucleus and cytoplasm. The long isoform of TLINC was associated with a migratory phenotype in iCCA cell lines and with the induction of proinflammatory cytokines, including interleukin 8, both in vitro and in resected human iCCA. TLINC was also identified as a tumor marker expressed in both epithelial and stroma cells. In nontumor livers, TLINC was only expressed in specific portal areas with signs of ductular reaction and inflammation. Finally, we provide experimental evidence of circular isoforms of TLINC, both in iCCA cells treated with TGF? and in resected human iCCA. Conclusion: We identify a novel TGF?-induced long noncoding RNA up-regulated in human iCCA and associated with an inflammatory microenvironment. (Hepatology Communications 2018;2:254-269).
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