Sonic hedgehog-mediated epithelial-mesenchymal transition in renal tubulointerstitial fibrosis

Bai, Yongheng; Lu, Hong; Lin, Chengcheng; Xu, Yaya; Hu, Dannü; Liang, Yong; Hong, Weilong; Chen, Bicheng

doi:10.3892/ijmm.2016.2546

Cited by 37 publications

(33 citation statements)

References 33 publications

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“…It has been shown that hypermethylation of Ptch1 is associated with the perpetuation of broblast activation and brosis in the liver [30] . Similarly, inhibition of Ptch1 may have pro-brotic effects in kidney tissue by activating Hh signaling [31,32]. Furthermore, Ptch1 gene mutations have been suggested to play an essential role in the pathogenesis of nephroblastoma [33].…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

Tang

Wang

Xie

et al. 2020

Preprint

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Background: The pathogenesis of renal fibrosis (RF) is not well understood. Here, we performed an integrative database analysis of miRNAs and mRNAs to discover the major regulatory pathway in RF.Methods: Putative miRNAs and mRNAs involved in RF in unilateral ureteral obstruction (UUO) model mice were extracted and analyzed using the Gene Expression Omnibus (GEO) database. The bioinformatics analysis suggested that Ptch1 expression is negatively regulated by miR-342-5p and FoxO3. Then real-time PCR, Western blot, Fluorescence in situ hybridization were done to confirm the hypothesis.Results: Sixty-three differentially expressed miRNAs (DE-miRNAs) in GSE118340, 141 DE-miRNAs in GSE42716, and 183 DE-mRNAs in GSE69101 were identified. Various bioinformatic analyses revealed miR-342-5p as a strong candidate regulator in RF. We also predicted that miR-342-5p targets Ptch1 and that FoxO3 is the transcription factor of Ptch1. We also observed that TGF-β1 upregulated the expression of miR-342-5p and inhibited the expression of FoxO3 and Ptch1 in TCMK-1 cells. Furthermore, downregulation of miR-342-5p or FoxO3 reversed the inhibitory effect of TGF-β1 on the expression of Ptch1 in TCMK-1 cells. Additionally, downregulation of Ptch1 increased TGF-β1-induced autophagy, as evidenced by an increase in the number of GFP-LC3 puncta and the increased protein expression of SOSTM1/p62 and LC3II/LC3I.Conclusion: Our findings showed that downregulation of Ptch1 induced autophagy in TGF-β1-stimulated TCMK-1 cells, and Ptch1 expression is negatively regulated by miR-342-5p and FoxO3. These findings will further our understanding of the molecular mechanisms of RF and provide useful novel therapeutic targets for RF.

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Section: Discussionmentioning

confidence: 99%

Negative Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

Tang

Wang

Xie

et al. 2020

Preprint

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“…As a result, the mesothelial cells produce TGF-β1, a key cytokine for EMT, progressively lose their epithelial characteristics and convert to a mesenchymal phenotype [21]. The cells attain mesenchymal characteristics, which include enhanced migratory capacity and increased extracellular matrix (ECM) production [5,8]. Previous studies found that ECM deposition plays an important role in the development of peritoneal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, interest in SHH signaling has expanded to its role in tissue fibrosis. Bai et al [8] reported that activation of the SHH signaling pathway promotes the EMT process and renal tubulointerstitial fibrosis. Ding et al [9] also demonstrated that SHH signaling plays a pivotal role in fibroblast activation and development of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, there is emerging evidence demonstrating that aberrant SHH signaling is implicated in the process of fibrogenesis in various tissues [8,13]. Therefore, investigating drugs to inhibit this pathway could help in the development of anti-fibrosis drugs.…”

Section: Itraconazole Attenuates Peritoneal Fibrosis Through Its Effementioning

confidence: 99%

“…The sonic hedgehog (SHH) signaling pathway regulates diverse aspects of embryonic development and plays an important role in organogenesis, tissue regeneration, and tissue repair [7][8][9]. This pathway is activated through the binding of the ligand SHH to its membrane receptor patched (PTCH).…”

Section: Itraconazole Attenuates Peritoneal Fibrosis Through Its Effementioning

confidence: 99%

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Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

et al. 2018

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Background: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. Methods: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. Results: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-β1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. Conclusion: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.

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Regulation of epithelial–mesenchymal transition via sonic hedgehog/glioma‐associated oncogene homolog 1 signaling pathway in peritoneal mesothelial cells

Wang

Ding

2020

Cell Biology International

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Sonic hedgehog (Shh) signaling regulating epithelial–mesenchymal transition (EMT) in cultured rat peritoneal mesothelial cells (PMCs) remains an under‐investigated topic. The current study aimed to elucidate the role of Shh signaling in the regulation of EMT in PMCs to attenuate peritoneal injury, with the view of enhancing the efficacy of peritoneal dialysis (PD). PMCs were initially extracted from male Wistar rats using pancreatic enzyme digestion. The expression of Shh and glioma‐associated oncogene homolog (Gli1) was quantitatively analyzed using the reverse‐transcription quantitative polymerase chain reaction (RT‐qPCR) and western blot analysis. Migration of PMCs was determined using Transwell assay. The expression of Shh, Gli1, and EMT markers including α‐smooth muscle actin (α‐SMA), fibronectin, collagen I, snail1, and E‐cadherin was examined by RT‐qPCR, western blot analysis, and immunofluorescence respectively. High glucose induction was identified to promote cell migration and increase the expression of Shh and Gli1 in a dose‐ and time‐dependent manner in rat PMCs. Cyclopamine (CPN) was observed to block the Shh signaling induced by high glucose, accompanied by cell migration inhibition, decreased expression of α‐SMA, fibronectin, collagen I and snail1 as well as increased expression of E‐cadherin. Altogether, overexpression of Gli1 by transfected Gli1 plasmid promotes cell migration and upregulates α‐SMA, fibronectin, Snail1, and collagen I expression, while downregulating E‐cadherin expression. Shh/Gli1 signaling is important in mediating EMT in rat PMCs, which provides a potential novel therapeutic approach for clinical investigation on renal failure treatment.

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Sonic hedgehog-mediated epithelial-mesenchymal transition in renal tubulointerstitial fibrosis

Cited by 37 publications

References 33 publications

Negative Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

Negative Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

Regulation of epithelial–mesenchymal transition via sonic hedgehog/glioma‐associated oncogene homolog 1 signaling pathway in peritoneal mesothelial cells

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