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

Area of Science:

• Nephrology
• Cell Biology
• Toxicology

Background:

• Cadmium (Cd²⁺) exposure is a known cause of chronic kidney disease and renal cancers.
• Cd²⁺-induced nephrotoxicity involves disrupted intracellular calcium (Ca²⁺) homeostasis, particularly within the endoplasmic reticulum (ER).
• The precise molecular mechanisms linking ER Ca²⁺ regulation to Cd²⁺-induced kidney damage remain incompletely understood.

Purpose of the Study:

• To elucidate the role of ER Ca²⁺ homeostasis in Cd²⁺-induced renal tubular cell injury.
• To investigate the involvement of sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) in Cd²⁺-induced nephrotoxicity.
• To identify potential therapeutic strategies targeting ER Ca²⁺ regulation for mitigating Cd²⁺-induced kidney damage.

Main Methods:

• Utilized mouse renal tubular cells (mRTEC) for in vitro studies.
• Investigated the effects of calcium-sensing receptor (CaSR) activation (NPS R-467), SERCA agonist (CDN1163), and SERCA2 overexpression.
• Examined the impact of proteasome inhibitor MG132 on Cd²⁺-treated cells.
• Assessed the expression of SERCA2 and phosphorylated phospholamban (p-PLB) in renal tubular cells.

Main Results:

• Activation of CaSR protected mRTEC against Cd²⁺ cytotoxicity by restoring ER Ca²⁺ homeostasis via SERCA.
• Cd²⁺-induced ER stress and apoptosis were attenuated by SERCA activation and SERCA2 overexpression.
• Cd²⁺ exposure reduced SERCA2 and p-PLB expression in renal tubular cells.
• Cd²⁺ promoted SERCA2 degradation through the proteasomal pathway, which was inhibited by MG132.

Conclusions:

• SERCA2 plays a critical role in maintaining ER Ca²⁺ balance and preventing Cd²⁺-induced apoptosis in renal tubular cells.
• The proteasomal degradation pathway is implicated in regulating SERCA2 stability under Cd²⁺ exposure.
• Targeting SERCA2 and the proteasome presents a promising therapeutic avenue for preventing Cd²⁺-induced cytotoxicity and renal injury.