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SDF?1/CXCR4 induces epithelial?mesenchymal transition through activation of the Wnt/??catenin signaling pathway in rat chronic allograft nephropathy.

ABSTRACT: Epithelial?mesenchymal transition (EMT) has been demonstrated to serve a crucial role in the progression of interstitial fibrosis, which is one of the principal pathological features of chronic allograft nephropathy (CAN). However, to the best of our knowledge, the mechanisms of EMT in CAN have not been investigated. In the present study, the effect of stromal cell?derived factor 1 (SDF?1) and the Wnt signaling pathway on the progression of EMT following kidney transplantation was investigated. The CAN model was established using Fisher 344 and Lewis rats, treated with low?dose cyclosporine with or without AMD3100. CAN was confirmed by the pathological alterations and chronic allograft damage index scoring, and EMT was confirmed by western blotting and reverse transcription?quantitative polymerase chain reaction. In the AMD3100 group, there were lower expression levels of ??SMA and higher expression levels of E?cadherin, which indicated that CAN and EMT were ameliorated by AMD3100. The kidney tissue was analyzed using an mRNA + long noncoding (lnc)RNA microarray. A total of 506 mRNAs and 404 lncRNAs were demonstrated to be significantly differentially expressed between the two groups, which revealed the involvement of SDF?1/CXC chemokine receptor 4 (CXCR4) and the Wnt pathway. SDF?1 was demonstrated to induce EMT in vitro through the upregulation of ??SMA, downregulation of E?cadherin and the wound healing assay, and in the rat renal tubular epithelial cells via the nuclear accumulation of ??catenin, which were all inhibited by either AMD3100 or DKK?1. CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt pathway, was downregulated following treatment with SDF?1, which was inhibited by AMD3100 but not by DKK?1. Thus, CXXC5 may be a regulator downstream of SDF?1/CXCR4 in EMT. In conclusion, SDF?1/CXCR4 induces EMT of renal tubular epithelial cells with the involvement of the Wnt pathway, which may be a novel mechanism and therapeutic target in kidney allograft fibrosis of rats.

SUBMITTER: Tang H

PROVIDER: S-EPMC6470988 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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SDF‑1/CXCR4 induces epithelial‑mesenchymal transition through activation of the Wnt/β‑catenin signaling pathway in rat chronic allograft nephropathy.

Tang Hao H Xu Yue Y Zhang Zijian Z Zeng Song S Dong Wenbo W Jiao Wenjiao W Hu Xiaopeng X

Molecular medicine reports 20190315 5

Epithelial‑mesenchymal transition (EMT) has been demonstrated to serve a crucial role in the progression of interstitial fibrosis, which is one of the principal pathological features of chronic allograft nephropathy (CAN). However, to the best of our knowledge, the mechanisms of EMT in CAN have not been investigated. In the present study, the effect of stromal cell‑derived factor 1 (SDF‑1) and the Wnt signaling pathway on the progression of EMT following kidney transplantation was investigated. ...[more]

PMID: 30896799

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Project description:BackgroundCigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Epithelial-mesenchymal transition (EMT) is an essential pathophysiological process in COPD and plays an important role in airway remodeling, fibrosis, and malignant transformation of COPD. Previous studies have indicated FERMT3 is downregulated and plays a tumor-suppressive role in lung cancer. However, the role of FERMT3 in COPD, including EMT, has not yet been investigated.MethodsThe present study aimed to explore the potential role of FERMT3 in COPD and its underlying molecular mechanisms. Three GEO datasets were utilized to analyse FERMT3 gene expression profiles in COPD. We then established EMT animal models and cell models through cigarette smoke (CS) or cigarette smoke extract (CSE) exposure to detect the expression of FERMT3 and EMT markers. RT-PCR, western blot, immunohistochemical, cell migration, and cell cycle were employed to investigate the potential regulatory effect of FERMT3 in CSE-induced EMT.ResultsBased on Gene Expression Omnibus (GEO) data set analysis, FERMT3 expression in bronchoalveolar lavage fluid was lower in COPD smokers than in non-smokers or smokers. Moreover, FERMT3 expression was significantly down-regulated in lung tissues of COPD GOLD 4 patients compared with the control group. Cigarette smoke exposure reduced the FERMT3 expression and induces EMT both in vivo and in vitro. The results showed that overexpression of FERMT3 could inhibit EMT induced by CSE in A549 cells. Furthermore, the CSE-induced cell migration and cell cycle progression were reversed by FERMT3 overexpression. Mechanistically, our study showed that overexpression of FERMT3 inhibited CSE-induced EMT through the Wnt/β-catenin signaling.ConclusionsIn summary, these data suggest FERMT3 regulates cigarette smoke-induced epithelial-mesenchymal transition through Wnt/β-catenin signaling. These findings indicated that FERMT3 was correlated with the development of COPD and may serve as a potential target for both COPD and lung cancer.

Dataset Information

SDF?1/CXCR4 induces epithelial?mesenchymal transition through activation of the Wnt/??catenin signaling pathway in rat chronic allograft nephropathy.

Publications

SDF‑1/CXCR4 induces epithelial‑mesenchymal transition through activation of the Wnt/β‑catenin signaling pathway in rat chronic allograft nephropathy.

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