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

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.