N-methyl-d-aspartate receptor 1 activation mediates cadmium-induced epithelial-mesenchymal transition in proximal tubular cells

Abstract

Cadmium (Cd) is a commonly found environmental pollutant and is known to damage multiple organs with kidneys being the most common one. N-methyl-d-aspartate receptor 1 (NMDAR1) is a ligand-gated ion channel that is highly permeable to calcium ion (Ca2+). Because Cd2+ and Ca2+ have structural and physicochemical similarities, whether and how Cd could interfere NMDAR1 function to cause renal epithelial cells dysfunction remains unknown. In this study, we investigated the role of NMDAR1 in Cd-induced renal damage and found that Cd treatment upregulated NMDAR1 expression and promoted epithelial-mesenchymal transition (EMT) in mouse kidneys in vivo and human proximal tubular epithelial HK-2 cells in vitro, which were accompanied with activation of the inositol-requiring enzyme 1 (IRE-1α) / spliced X box binding protein-1 (XBP-1s) pathway, an indicative of endoplasmic reticulum (ER) stress. Mechanistically, NMDAR1 upregulation by Cd promoted Ca2+ channel opening and Ca2+ influx, resulting in ER stress and subsequently EMT in HK-2 cells. Inhibition of NMDAR1 by pharmacological antagonist MK-801 significantly attenuated Cd-induced Ca2+ influx, ER stress, and EMT. Pretreatment with the IRE-1α/XBP-1s pathway inhibitor STF-083010 also restored the epithelial phenotype of Cd-treated HK-2 cells. Therefore, our findings suggest that NMDAR1 activation mediates Cd-induced EMT in proximal epithelial cells likely through the IRE-1α/XBP-1s pathway, supporting the idea that NMDAR1 could be a potential therapeutic target for Cd-induced renal damage.