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

Sep 24, 2026

Cadmium (Cd2+) exposure triggers chronic kidney disease and renal cancer through injury of renal tubular cells, with cytotoxicity linked to disrupted intracellular Ca2+ homeostasis governed by the endoplasmic reticulum (ER). The study identifies a CaSR-dependent mechanism where NPS R-467 restores ER Ca2+ homeostasis via SERCA to protect renal tubular cells. Cd2+-induced ER stress and apoptosis are blocked by SERCA agonism and SERCA2 overexpression. Cd2+ also lowers SERCA2 and p-PLB activity while promoting proteasomal degradation of SERCA2; proteasome inhibition prevents this reduction, supporting SERCA2 and proteasome targeting as a therapeutic strategy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

1. Introduction

2. Results

2.1. NPS R-467 Protects against Cd2+-Induced Apoptosis Associated with Restoring Cytosolic Ca2+ Homeostasis

Article Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells Kongdong Li 1,†, Chuanzhi Guo 1,†, Jiacheng Ruan 1, Bo Ning 1, Chris Kong-Chu Wong 2, Haifeng Shi 1 and Jie Gu 1, * Citation: Li, K.; Guo, C.; Ruan, J.; Ning, B.; Wong, C.K.-C.; Shi, H.; Gu, J. Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells. Int. J. Mol. Sci. 2023, 24, 5979 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24065979 Academic Editor: Takuya Noguchi Received: 2 March 2023 Revised: 16 March 2023 Accepted: 20 March 2023 Published: 22 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 School of Life Sciences, Jiangsu University, Zhenjiang 212013, China 2 Department of Biology, Hong Kong Baptist University, Hong Kong SAR, China * Correspondence: [1000004531@ujs.edu.cn](1000004531@ujs.edu.cn); Tel.: +86-0511-88791923 † These authors contributed equally to this work. 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+ exposureinduced 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: ER stress; Ca2+; apoptosis; cadmium 1. Introduction Cadmium (Cd), as a widely distributed environmental pollutant, is unavoidably absorbed by humans through environmental and occupational exposures [1] . After intake into the human body, approximately 50% Cd as the divalent cation (Cd2+ ) accumulatesin the kidney, in which the renal proximal tubule is the ﬁrst opportunistic site of Cd2+ reabsorption following plasma ﬁltration in the glomerulus. Previous studies have tried to explore the potential mechanism of Cd2+-induced cytotoxicity of the renal proximal tubule cells, which will help ﬁnd potential intoxication targets and explore novel renoprotective strategies [2,3] . However, primary cellular events and key effector molecules of Cd2+ -induced cytotoxicity remain unclear. Cd2+-disrupted intracellular calcium (Ca2+ ) homeostasis induced autophagy inhibition, promoted oxidative stress, and thereby

FAQs

What key mechanism does cadmium disrupt in renal proximal tubular cells?

Cadmium disrupts intracellular Ca2+ homeostasis by disturbing ER Ca2+ regulation, leading to ER stress and apoptosis in renal tubular cells.

How does SERCA2 relate to cadmium-induced toxicity?

Cadmium reduces SERCA2 expression and activity, contributing to ER Ca2+ imbalance. The study shows ER stress and apoptosis are effectively suppressed by SERCA agonists and SERCA2 overexpression.

What role does the proteasomal pathway play in SERCA2 regulation under cadmium exposure?

Cadmium promotes proteasome-mediated degradation of SERCA2, lowering its stability; proteasome inhibition with MG132 suppresses this reduction.

Sep 24, 2026

Upload by Lucas Martin