Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells

Abstract

Cadmium (Cd²⁺) exposure induces chronic kidney disease and renal cancers, which originate from injury and cancerization of renal tubular cells. Previous studies have shown that Cd²⁺ induced cytotoxicity by disrupting the intracellular Ca²⁺ homeostasis that is physically regulated by the endoplasmic reticulum (ER) Ca²⁺ store. However, the molecular mechanism of ER Ca²⁺ homeostasis in Cd²⁺-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 Cd²⁺ exposure-induced cytotoxicity of mouse renal tubular cells (mRTEC) by restoring ER Ca²⁺ homeostasis through the ER Ca²⁺ reuptake channel sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA). Cd²⁺-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 Cd²⁺ reduced the expressions of SERCA2 and its activity regulator phosphorylation phospholamban (p-PLB) in renal tubular cells. Cd²⁺-induced SERCA2 degradation was suppressed by the treatment of proteasome inhibitor MG132, which suggested that Cd²⁺ reduced SERCA2 protein stability by promoting the proteasomal protein degradation pathway. These results suggested that SERCA2 played pivotal roles in Cd²⁺-induced ER Ca²⁺ 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 Cd²⁺-induced cytotoxicity and renal injury.

Keywords: Ca2+; ER stress; apoptosis; cadmium.