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

Xu, Yanyan; Wang, Jing; Ding, Hong

doi:10.1002/cbin.11363

Cited by 4 publications

(5 citation statements)

References 29 publications

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“…Consistently, the inhibition of Shh signaling by CPN could selectively block the proliferation of fibroblasts ( Figure 6 ). Zhou et al ( 39 , 42 ) showed that in different types of CKD, Shh specifically upregulated in renal tubular epithelial cells. It activated mesenchymal fibroblasts and promoted their proliferation through various mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Shh also promoted the expression of FN and Vimentin and mediated the deposition of ECM ( 39 ). In ischaemia reperfusion injury (IRI) mouse model ( 39 , 42 ), overexpression of Shh promoted the proliferation of fibroblasts and ECM overproduction and deposition, eventually leading to kidney fibrosis and aggravated kidney function damage. Fabian et al demonstrated that recombinant Shh protein activated Ptch1/Gli1 signaling pathways in fibroblasts and induced the expression of α-smooth muscle actin (α-SMA), FN, and type I collagen, suggesting that Shh signal transduction activated fibroblasts to synthesize ECM ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

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Senescent renal tubular epithelial cells activate fibroblasts by secreting Shh to promote the progression of diabetic kidney disease

Wang

Chen

et al. 2023

Front. Med.

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IntroductionDiabetic kidney disease (DKD) is one of the complications of diabetes; however, the pathogenesis is not yet clear. A recent study has shown that senescence is associated with the course of DKD. In the present study, we explored whether senescent renal tubular cells promote renal tubulointerstitial fibrosis by secreting Sonic hedgehog (Shh) which mediates fibroblast activation and proliferation in DKD.MethodsA 36-week-old db/db mice model and the renal tubular epithelial cells were cultured in high glucose (HG, 60 mmol/L) medium for in vivo and in vitro experiments.ResultsCompared to db/m mice, blood glucose, microalbuminuria, serum creatinine, urea nitrogen, and UACR (microalbuminuria/urine creatinine) were markedly increased in db/db mice. Collagen III, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) were also increased in db/db mice kidneys, suggesting fibrosis and inflammation in the organ. Moreover, the detection of SA-β-galactosidase (SA-β-Gal) showed that the activity of SA-β-Gal in the cytoplasm of renal tubular epithelial cells increased, and the cell cycle inhibition of the expression of senescence-related gene cell cycle inhibitor p16INK4A protein and p21 protein increased, indicating that renal fibrosis in db/db mice was accompanied by cell senescence. Furthermore, Shh is highly expressed in the injured renal tubules and in the kidney tissue of db/db mice, as detected by enzyme-linked immunosorbent assay (ELISA). The results of immunofluorescence staining showed increased positive staining for Shh in renal tubular epithelial cells of db/db mice and decreased positive staining for Lamin B1, but increased positive staining for γH2A.X in cells with high Shh expression; similar results were obtained in vitro. In addition, HG stimulated renal tubular epithelial cells to secrete Shh in the supernatant of the medium. D-gal treatment of renal tubular epithelial cells increased the protein levels of Shh and p21. We also found enhanced activation and proliferation of fibroblasts cultured with the supernatant of renal tubular epithelial cells stimulated by HG medium but the proliferative effect was significantly diminished when co-cultured with cyclopamine (CPN), an inhibitor of the Shh pathway.DiscussionIn conclusion, HG induces renal tubular epithelial cell senescence, and the secretion of senescence-associated proteins and Shh mediates inflammatory responses and fibroblast activation and proliferation, ultimately leading to renal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Senescent renal tubular epithelial cells activate fibroblasts by secreting Shh to promote the progression of diabetic kidney disease

Wang

Chen

et al. 2023

Front. Med.

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“…The experiments prove that BMSCs can reduce the AKI degree. However, some articles mentioned significant increase of Gli1+ MSCs in the medulla, cortex and around the entire renal artery in AKI caused by DDP and tamoxifen, most Gli1+ cells up-regulated the expression of α-SMA and GLI1+ BMSC accumulate around blood vessels after injury, which increased the risk of fibrosis [ 11 , 12 ]. Moreover, in the study of using BMSCs to treat pulmonary fibrosis, it was also found that the degree of pulmonary fibrosis can be inhibited by reducing Gli1.…”

Section: Discussionmentioning

confidence: 99%

“…According to research findings, when BMSCs were used to treat mice with AKI, the number of Gli1 + MSCs significantly increased in the renal medulla, renal cortex and around the entire renal artery. Moreover, the Gli1 + cells can up-regulate the expression of a-SMA and promote fibrosis development, i.e., there is the risk of promoting fibrosis during treatment of AKI using BMSCs [ 11 , 12 ]. However, there are no studies on how Gli1 regulates BMSCs to promote fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Gliko BMSC: A potential strategy of treatment for renal fibrosis

Shi

Gao

et al. 2022

Regenerative Therapy

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“…The Hedgehog (Hh) signalling pathway is involved in cell cycle regulation and proliferation, cell adhesion and survival, EMT, self-renewal, and angiogenesis. 14 , 15 Many clinical studies have confirmed that Hh signalling is abnormally activated in lung adenocarcinoma, breast cancer, liver cancer, and other tumours, and is closely related to tumour development, prognosis, and drug resistance. 16 - 19 Hedgehog protein homologues, including sonic hedgehog (SHH), desert hedgehog (DHH), and Indian hedgehog (IHH), are highly expressed in the gastrointestinal tract, and the SHH protein is increased in gastric lesions and gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

PKNOX1 acts as a transcription factor of DHH and promotes the progression of stomach adenocarcinoma by regulating the Hedgehog signalling pathway

Liu,

Zhao,

Liu

2023

Int J Immunopathol Pharmacol

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Background: This study explored the effects and potential mechanism by which PBX/knotted 1 homeobox 1 (PKNOX1) may exacerbate stomach adenocarcinoma (STAD). Methods: For the in silico analysis, we examined TCGA-PKNOX1 expression using the UALCAN website, as well as its expression patterns in the GSE172032 and GSE174237 datasets, obtained from the GEO database. The associated patient survival curves, were analysed via the KMplot webtool. In vitro, we measured cell viability, proliferation, migration, and invasion using cell counting kit-8, colony formation, wound healing, and cell migration assays, respectively. Real time qPCR and western blotting assessed the mRNA and protein levels of PKNOX1, Snail, vimentin, N-cadherin, E-cadherin, desert hedgehog (DHH), cyclin D2, glioma-associated oncogene homolog 1, and smoothened. Gene Set Enrichment Analysis was performed using LinkedOmics webtools and the clusterProfiler package in R. Dual-luciferase reporter assay was used to examine the interactions of PKNOX1 with DHH, and of TEA domain transcription factor 4 (TEAD4) with PKNOX1. Results: PKNOX1 was highly expressed in STAD and linked to poor patient survival. Downregulation of PKNOX1 inhibited STAD cell viability, proliferation, migration, invasion, and epithelial-mesenchymal transition. Upregulation of TEAD4 promoted colony formation and migration, while these effects were reversed by PKNOX1 depletion. Furthermore, PKNOX1 regulated the activation of the hedgehog signalling pathway at the gene level, as we identified PKNOX1 to be a putative transcription factor for DHH that promotes its expression. Conclusion: Our results show that PKNOX1 acts as a candidate transcription factor for DHH and facilitates STAD development by regulating the hedgehog signalling pathway.

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

Cited by 4 publications

References 29 publications

Senescent renal tubular epithelial cells activate fibroblasts by secreting Shh to promote the progression of diabetic kidney disease

Senescent renal tubular epithelial cells activate fibroblasts by secreting Shh to promote the progression of diabetic kidney disease

Gliko BMSC: A potential strategy of treatment for renal fibrosis

PKNOX1 acts as a transcription factor of DHH and promotes the progression of stomach adenocarcinoma by regulating the Hedgehog signalling pathway

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