Caveolin-1 Stabilizes SERCA2 to Counteract Acute Kidney Injury via Suppression of Ca2+-Dependent Endoplasmic Reticulum Stress in Distal Tubules

  • Adv Sci (Weinh). 2026 May 8:e75449. doi: 10.1002/advs.75449.
Yan Zhang  1  2  3  4 ,  Xin He  1  2  3  4 ,  Hao Huang  1  2  3  5 ,  Rong Lu  1  6 ,  Xin Lv  1  2  7 ,  Shenglan Li  1  2  3  8 ,  Sijue Zou  1  2  3  4 ,  Jiawei Cheng  1  2  3  4 ,  Yiwei Xiong  1  2  3  4 ,  Zhenghao Deng  2  9 ,  Qiongjing Yuan  1  2  4  10 ,  Yanyun Xie  1  2  4  10 ,  Ling Huang  1  2  4  10 ,  Jiaxi Pu  1  2  4  10 ,  Shao Liu  4  11 ,  Qianbin Li  2  12 ,  Jie Meng  2  13 ,  Huixiang Yang  2  14 ,  Lijian Tao  1  2  3  4 ,  Zhangzhe Peng  1  2  4  10
Affiliations
  • 1. Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China.
  • 2. Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, China.
  • 3. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
  • 4. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, China.
  • 5. Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China.
  • 6. Health Management Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China.
  • 7. Department of Nuclear Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China.
  • 8. Department of Ultrasound, Xiangya Hospital, Central South University, Changsha, China.
  • 9. Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
  • 10. FuRong Laboratory, Changsha, China.
  • 11. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
  • 12. Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
  • 13. Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha, China.
  • 14. Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China.
PMID: 42102380 DOI: 10.1002/advs.75449
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 (CA2+) homeostasis imbalance and endoplasmic reticulum (ER) stress in injured kidney tissues. Mechanistically, Cav-1 interacts with sarcoplasmic/endoplasmic reticulum CA2+-ATPase 2 (SERCA2), a key regulator of intracellular CA2+ homeostasis, through its scaffolding domain, promoting SERCA2 deubiquitination and stability in the ER, thereby maintaining intracellular CA2+ 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.

Keywords
Cav‐1; ER stress; SERCA2; acute kidney injury; calcium homeostasis.
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