Endosulfan induced kidney cell injury by modulating ACE2 through up-regulating miR-429 in HK-2 cells. (15th January 2023)

• Record Type: Journal Article
• Authors: Zhang, Boxiang; Liu, Shiwen; Sun, Yeqing; Xu, Dan
• Is Part Of: Toxicology. Volume 484(2023)
• Publication Date: 2023-01-15
• Subjects: Endosulfan -- MiR-429 -- ACE2 -- Apoptosis -- Inflammation -- EMT; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2022.153392
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: Endosulfan, a typical organochlorine pesticide, is widely used in agricultural countries and was detected in blood samples from the general population. Studies have shown a positive correlation between chronic kidney disease of unknown aetiology (CKDu) and endosulfan. CKDu has become endemic in agricultural countries, with clinical manifestations of tubulointerstitial fibrosis.The goal of this study was to investigate the effects of endosulfan in kidney cell injury in human renal tubular epithelial cells (HK-2), focusing on apoptosis, inflammatory response, and epithelial-mesenchymal transition (EMT). We found that endosulfan induced apoptosis in HK-2 cells by up-regulating the expression of BAX, APAF-1, Caspase-3 and mitochondrial Cytochrome c was released into the cytosol. Endosulfan caused an inflammatory response, showing the increase in the secretion and mRNA expression levels of IL-6/IL-8. Endosulfan triggered EMT, characterized by downregulation of E-cadherin and upregulation of Vimentin. Western blot results showed that p-Smad3 and Smad3 protein expression were elevated while the expression of Smad7 were decreased in endosulfan-exposed groups. Dual luciferase reporter assay confirmed the potential binding capacity of miR-429 to 3'-UTR of ACE2. Endosulfan causes upregulation of miR-429 and downregulation of ACE2 in HK-2 cells. Overexpression of miR-429 or silencing of ACE2 in HK-2 cells caused apoptosis, inflammation and EMT through TGF signaling pathway. These findings suggest that endosulfan can lead to kidney cell injury by modulating ACE2 through up-regulating miR-429, providing new evidence for the pathogenesis of CKDu. Graphical Abstract: ga1 Highlights: Endosulfan induced apoptosis via mitochondrial apoptotic pathway in HK-2 cells. Endosulfan activated TGF-β/smad signalling pathway to trigger EMT in HK-2 cells. Endosulfan induced inflammatory responses in HK-2 cells. Endosulfan caused renal cell injury by modulating miR-429 and ACE2.