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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.",{"@graph":69,"@context":121},[70,84,104],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/cadmium-disrupted-er-ca2-homeostasis-by-inhibiting-serca2-expression-and-activity-to-induce-apoptosis-in-renal-proximal-tubular-cells/377703/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/cadmium-disrupted-er-ca2-homeostasis-by-inhibiting-serca2-expression-and-activity-to-induce-apoptosis-in-renal-proximal-tubular-cells/377703.png","ImageObject",300,407,{"name":92,"@type":93},"Lucas Martin","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-24",true,{"@type":101,"interactionType":102,"userInteractionCount":14},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"What key mechanism does cadmium disrupt in renal proximal tubular cells?","Question",{"text":111,"@type":112},"Cadmium disrupts intracellular Ca2+ homeostasis by disturbing ER Ca2+ regulation, leading to ER stress and apoptosis in renal tubular cells.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"How does SERCA2 relate to cadmium-induced toxicity?",{"text":116,"@type":112},"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.",{"name":118,"@type":109,"acceptedAnswer":119},"What role does the proteasomal pathway play in SERCA2 regulation under cadmium exposure?",{"text":120,"@type":112},"Cadmium promotes proteasome-mediated degradation of SERCA2, lowering its stability; proteasome inhibition with MG132 suppresses this reduction.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},377703,1790247128,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},8796095360427,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Article  \nCadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells  \nKongdong Li 1,†, Chuanzhi Guo 1,†, Jiacheng Ruan 1, Bo Ning 1, Chris Kong-Chu Wong 2, Haifeng Shi 1 and Jie Gu 1, *  \nCitation: 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  \nAcademic Editor: Takuya Noguchi  \nReceived: 2 March 2023  \nRevised: 16 March 2023  \nAccepted: 20 March 2023  \nPublished: 22 March 2023  \nCopyright: © 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/)) .  \n1 School of Life Sciences, Jiangsu University, Zhenjiang 212013, China  \n2 Department of Biology, Hong Kong Baptist University, Hong Kong SAR, China  \n* Correspondence: [1000004531@ujs.edu.cn](1000004531@ujs.edu.cn); Tel.: +86-0511-88791923 † These authors contributed equally to this work.  \nAbstract: 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.  \nKeywords: ER stress; Ca2+; apoptosis; cadmium  \n1. Introduction  \nCadmium (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.  \nCd2+-disrupted intracellular calcium (Ca2+ ) homeostasis induced autophagy inhibition, promoted oxidative stress, and thereby ","cbCaiquWRkleMLZN","https://ap.wps.com/l/cbCaiquWRkleMLZN","pdf",2645177,14,"English","# Abstract\n# 1. Introduction\n# 2. Results\n## 2.1. NPS R-467 Protects against Cd2+-Induced Apoptosis Associated with Restoring Cytosolic Ca2+ Homeostasis","[{\"question\":\"What key mechanism does cadmium disrupt in renal proximal tubular cells?\",\"answer\":\"Cadmium disrupts intracellular Ca2+ homeostasis by disturbing ER Ca2+ regulation, leading to ER stress and apoptosis in renal tubular cells.\"},{\"question\":\"How does SERCA2 relate to cadmium-induced toxicity?\",\"answer\":\"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.\"},{\"question\":\"What role does the proteasomal pathway play in SERCA2 regulation under cadmium exposure?\",\"answer\":\"Cadmium promotes proteasome-mediated degradation of SERCA2, lowering its stability; proteasome inhibition with MG132 suppresses this reduction.\"}]","Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells | PDF",1790226746,35]