Arsenic induces fibrogenic changes in human kidney epithelial cells potentially through epigenetic alterations in DNA methylation

• Published in: Journal of cellular physiology Vol. 234; no. 4; pp. 4713 - 4725
• Main Authors: Chang, Yu‐Wei, Singh, Kamaleshwar P.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2019
• Subjects: Actin; AKT; AKT protein; Arsenic; Arsenites - toxicity; Cell Line; Cell Proliferation - drug effects; chronic kidney disease; Collagen (type I); Contamination; CpG islands; Decitabine - pharmacology; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - drug effects; DNA Modification Methylases - antagonists & inhibitors; DNA Modification Methylases - metabolism; Enzyme Inhibitors - pharmacology; Epidemiology; Epigenesis, Genetic - drug effects; Epigenetics; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial-Mesenchymal Transition - drug effects; epithelial–mesenchymal transition; Exposure; Fibronectin; Fibrosis; Gene expression; Gene Expression Regulation; Genes; Growth factors; Humans; Inhibitors; Kidney diseases; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Matrix metalloproteinase; Mesenchyme; Metalloproteinase; Morphology; Muscles; Public health; Signal Transduction; Smooth muscle; Sodium Compounds - toxicity; TGF‐β; Time Factors; TIMP‐3; Tissue inhibitor of metalloproteinases; Transforming growth factor; Transforming growth factor-b; TIMP-3; chronic kidney disease; DNA methylation; TGF-β; AKT; epithelial-mesenchymal transition; fibrosis; arsenic
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27244

Arsenic contamination is a significant public health issue, and kidney is one of the target organ for arsenic‐induced adverse effects. Renal fibrosis is a well‐known pathological stage frequently observed in progressive chronic kidney disease (CKD). Epidemiological studies implicate arsenic exposure to CKD, but the role of arsenic in kidney fibrosis and the underlying mechanism is still unclear. It is in this context that the current study evaluated the effects of long‐term arsenic exposure on the cellular response in morphology, and marker genes expression with respect to fibrosis using human kidney 2 (HK‐2) epithelial cells. Results of this study revealed that in addition to increased growth, HK‐2 cells underwent phenotypic, biochemical and molecular changes indicative of epithelial–mesenchymal transition (EMT) in response to the exposure to arsenic. Most importantly, the arsenic‐exposed cells acquired the pathogenic features of fibrosis as supported by increased expression of markers for fibrosis, such as Collagen I, Fibronectin, transforming growth factor β, and α‐smooth muscle actin. Upregulation of fibrosis associated signaling molecules such as tissue inhibitor of metalloproteinases‐3 and matrix metalloproteinase‐2 as well as activation of AKT was also observed. Additionally, the expression of epigenetic genes (DNA methyltransferases 3a and 3b; methyl‐CpG binding domain 4) was increased in arsenic‐exposed cells. Treatment with DNA methylation inhibitor 5‐Aza‐2′‐dC reversed the EMT properties and restored the level of phospho‐AKT. Together, these data for the first time suggest that long‐term exposure to arsenic can increase the risk of kidney fibrosis. Additionally, our data suggest that the arsenic‐induced fibrotic changes are, at least in part, mediated by DNA methylation and therefore potentially can be reversed by epigenetic therapeutics. Although the epidemiological evidence implicates arsenic exposure to chronic kidney disease, the role of arsenic in kidney fibrosis is still unclear. In this context, the findings of this study, for the first time, revealed that chronic exposure to arsenic can increase the risk of kidney fibrosis. Our data also suggest that the arsenic‐induced fibrotic changes in kidney epithelial cells are, at least in part, mediated by epigenetic mechanism of DNA methylation and therefore potentially can be reversed by epigenetic therapeutics.