Supplementation with a cell-permeable Cav-1 scaffolding domain peptide or activation of SERCA2 with CDN1163 alleviates ischemia/reperfusion- and LPS-induced acute kidney injury.
Does supplementation with Cav-1 scaffolding domain peptide or SERCA2 activation alleviate acute kidney injury in preclinical models?
Cav-1 protects against acute kidney injury by stabilizing SERCA2 to maintain calcium homeostasis and suppress ER stress, highlighting a potential therapeutic target.
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.
Zhang et al. (Fri,) conducted a other in Acute kidney injury (AKI). Cav-1 scaffolding domain peptide (CSP) or SERCA2 agonist CDN1163 was evaluated on AKI severity (IRI- and LPS-induced). Supplementation with a cell-permeable Cav-1 scaffolding domain peptide or activation of SERCA2 with CDN1163 alleviates ischemia/reperfusion- and LPS-induced acute kidney injury.