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journal article·2026-07Open access

Caveolin‐1 Stabilizes SERCA2 to Counteract Acute Kidney Injury via Suppression of Ca 2+ ‐Dependent Endoplasmic Reticulum Stress in Distal Tubules

Yan Zhang, Xin He, Hao Huang, Rong Lu, Xin Lv, Shenglan Li, Sijue Zou, Jiawei Cheng, Yiwei Xiong, Zhenghao Deng, Qiongjing Yuan, Yanyun Xie, Ling Huang, Jiaxi Pu, Shao Liu, Qianbin Li, Jie Meng, Huixiang Yang, Lijian Tao, Zhangzhe Peng

Advanced Science· Volume 13· Issue 42
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Source abstract

Abstract

ABSTRACT Acute kidney injury (AKI) is a severe clinical condition with high morbidity and mortality. Caveolin‐1 (Cav‐1), a main structural protein of caveolae, orchestrates key cellular processes including endocytosis, lipid transport, and signal transduction by serving as a platform. However, its specific role in AKI remains unclear. Here, we report that Cav‐1 is upregulated in distal tubule epithelial cells (TECs) in both AKI patients and mouse models induced by ischemia/reperfusion injury (IRI) and lipopolysaccharide (LPS). Global and distal TEC‐specific Cav1 knockout exacerbates IRI and LPS‐induced AKI. RNA‐seq reveals that Cav‐1 deficiency exacerbates intracellular calcium ion (Ca 2+ ) homeostasis imbalance and endoplasmic reticulum (ER) stress in injured kidney tissues. Mechanistically, Cav‐1 interacts with sarcoplasmic/endoplasmic reticulum Ca 2+ ‐ATPase 2 (SERCA2), a key regulator of intracellular Ca 2+ homeostasis, through its scaffolding domain, promoting SERCA2 deubiquitination and stability in the ER, thereby maintaining intracellular Ca 2+ homeostasis and suppressing ER stress in distal TECs. Furthermore, supplementation with a cell‐permeable Cav‐1 scaffolding domain peptide (CSP) or activation of SERCA2 with a small‐molecule agonist CDN1163 alleviates IRI‐ and LPS‐induced AKI, while distal TEC‐specific SERCA2 knockdown abrogates CSP's therapeutic effect. Together, these findings reveal a novel Cav‐1‐mediated pathway and highlight its potential as a therapeutic target for AKI.
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Research context

OpenAlex topics: Caveolin-1 and cellular processes · Cardiac electrophysiology and arrhythmias · Magnesium in Health and Disease

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Nephrology Xiangya Hospital Central South University Changsha China

Hunan Key Laboratory of Organ Fibrosis Central South University Changsha China

National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha China

National Medical Metabolomics International Collaborative Research Center Xiangya Hospital Central South University Changsha China

Department of Cell Biology School of Life Sciences Central South University Changsha China

Health Management Center Hunan Provincial People's Hospital The First Affiliated Hospital of Hunan Normal University Changsha China

Department of Nuclear Medicine Hunan Provincial People's Hospital The First Affiliated Hospital of Hunan Normal University Changsha China

Department of Ultrasound Xiangya Hospital Central South University Changsha China

Department of Pathology Xiangya Hospital Central South University Changsha China

FuRong Laboratory Changsha China

Department of Pharmacy Xiangya Hospital Central South University Changsha China

Department of Medicinal Chemistry Xiangya School of Pharmaceutical Sciences Central South University Changsha China

Department of Pulmonary and Critical Care Medicine Third Xiangya Hospital Central South University Changsha China

Department of Gastroenterology Xiangya Hospital Central South University Changsha China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Hunan Province

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