Dysregulations of miR-503-5p and Wnt/β-catenin pathway coordinate in mediating cadmium-induced kidney fibrosis

• Published in: Ecotoxicology and environmental safety 2021-11, Vol.224, p.112667, Article 112667
• Main Authors: Liang, Lixia, Huang, Ke, Yuan, Wenya, Liu, Lili, Zou, Fei, Wang, Guanghai
• Format: Article
• Language: English
• Subjects: Cadmium; Epithelial-mesenchymal transition; Kidney fibrosis; MiR-503-5p; Wnts
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2021.112667

Cadmium is a severe environmental pollutant that mainly targets kidney and causes kidney disease in the end. However, the mechanism of cadmium-induced kidney disease is still unclear. In this study, we treated SD rats, kidney epithelial or fibroblast cells with cadmium, and examined the renal fibrosis process and underlying cellular and molecular mechanism. Rats received daily (Monday-Friday) subcutaneous injections of CdCl2, 0.6 mg/kg, for 6 weeks or 12 weeks, and NRK-52E cells were treated with CdCl2 of 8 μM for 24 h. Sirius red staining and immunohistochemistry assay showed that sub-chronic exposure to cadmium caused interstitial fibrosis in rat kidneys. Cell experiments showed that cadmium treatment in NRK-52E cells only changed levels of α-SMA, vimentin and E-cadherin, but not collagen1, indicating that cells other than EMT cells might be responsible for the extracellular matrix production. By contrast, co-culture of NRK-49F cells with cadmium-treated NRK-52E cells produced collagen1. Assays of supernatant of NRK-52E cell culture showed that the secreted Wnt1, Wnt4 were increased, while miR-503-5p was decreased by cadmium treatment. RT-QPCR assay found that miR-503-5p was downregulated in both kidney of rats and NRK-52E cells exposed to cadmium. miR-503-5p was further shown to be competent in hindering epithelial-mesenchymal transition and fibroblast activation. Given the well established involvement of Wnt/β-catenin pathway in fibrosis, this study suggested that dysregulations of Wnts and miR-503-5p coordinate in mediating cadmium-induced kidney fibrosis. Our findings might provide new insight in the cellular and molecular mechanisms of kidney interstitial fibrosis and novel therapeutic targets for cadmium-induced kidney disease. [Display omitted] •Cd can induce renal fibrosis in rats.•Cd-induced EMT promotes activation of renal fibroblast through secreted molecules.•More Wnts and less miR-503-5p secreted from renal tubular cells undergoing Cd-induced EMT lead to fibroblast activation.