Cadmium Disrupted ER Ca 2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells.

Cadmium (Cd) exposure induces chronic kidney disease and renal cancers, which originate from injury and cancerization of renal tubular cells. Previous studies have shown that Cd induced cytotoxicity by disrupting the intracellular Ca homeostasis that is physically regulated by the endoplasmic reticulum (ER) Ca store. However, the molecular mechanism of ER Ca homeostasis in Cd-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 exposure-induced cytotoxicity of mouse renal tubular cells (mRTEC) by restoring ER Ca homeostasis through the ER Ca reuptake channel sarco/endoplasmic reticulum Ca-ATPase (SERCA). Cd-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 reduced the expressions of SERCA2 and its activity regulator phosphorylation phospholamban (p-PLB) in renal tubular cells. Cd-induced SERCA2 degradation was suppressed by the treatment of proteasome inhibitor MG132, which suggested that Cd reduced SERCA2 protein stability by promoting the proteasomal protein degradation pathway. These results suggested that SERCA2 played pivotal roles in Cd-induced ER Ca 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-induced cytotoxicity and renal injury.