Abstract
Cadmium (Cd(2+)) exposure induces chronic kidney disease and renal cancers, which originate from injury and cancerization of renal tubular cells. Previous studies have shown that Cd(2+) induced cytotoxicity by disrupting the intracellular Ca(2+) homeostasis that is physically regulated by the endoplasmic reticulum (ER) Ca(2+) store. However, the molecular mechanism of ER Ca(2+) homeostasis in Cd(2+)-induced nephrotoxicity remains unclear. In this study, our results firstly revealed that the activation of calcium-sensing receptor (CaSR) by NPS R-467 could protect against Cd(2+) exposure-induced cytotoxicity of mouse renal tubular cells (mRTEC) by restoring ER Ca(2+) homeostasis through the ER Ca(2+) reuptake channel sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA). Cd(2+)-induced ER stress and cell apoptosis were effectively abrogated by SERCA agonist CDN1163 and SERCA2 overexpression. In addition, in vivo, and in vitro results proved that Cd(2+) reduced the expressions of SERCA2 and its activity regulator phosphorylation phospholamban (p-PLB) in renal tubular cells. Cd(2+)-induced SERCA2 degradation was suppressed by the treatment of proteasome inhibitor MG132, which suggested that Cd(2+) reduced SERCA2 protein stability by promoting the proteasomal protein degradation pathway. These results suggested that SERCA2 played pivotal roles in Cd(2+)-induced ER Ca(2+) imbalance and stress to contribute to apoptosis of renal tubular cells, and the proteasomal pathway was involved in regulating SERCA2 stability. Our results proposed a new therapeutic approach targeting SERCA2 and associated proteasome that might protect against Cd(2+)-induced cytotoxicity and renal injury.