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Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells
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 endopl...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053525/ https://www.ncbi.nlm.nih.gov/pubmed/36983052 http://dx.doi.org/10.3390/ijms24065979 |
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author | Li, Kongdong Guo, Chuanzhi Ruan, Jiacheng Ning, Bo Wong, Chris Kong-Chu Shi, Haifeng Gu, Jie |
author_facet | Li, Kongdong Guo, Chuanzhi Ruan, Jiacheng Ning, Bo Wong, Chris Kong-Chu Shi, Haifeng Gu, Jie |
author_sort | Li, Kongdong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10053525 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100535252023-03-30 Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells Li, Kongdong Guo, Chuanzhi Ruan, Jiacheng Ning, Bo Wong, Chris Kong-Chu Shi, Haifeng Gu, Jie Int J Mol Sci Article 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. MDPI 2023-03-22 /pmc/articles/PMC10053525/ /pubmed/36983052 http://dx.doi.org/10.3390/ijms24065979 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Li, Kongdong Guo, Chuanzhi Ruan, Jiacheng Ning, Bo Wong, Chris Kong-Chu Shi, Haifeng Gu, Jie Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells |
title | Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells |
title_full | Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells |
title_fullStr | Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells |
title_full_unstemmed | Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells |
title_short | Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells |
title_sort | cadmium disrupted er ca(2+) homeostasis by inhibiting serca2 expression and activity to induce apoptosis in renal proximal tubular cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053525/ https://www.ncbi.nlm.nih.gov/pubmed/36983052 http://dx.doi.org/10.3390/ijms24065979 |
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