Annexin A1 contributes to fibroblast activation in kidney fibrosis via regulating YAP-mediated autophagy

Kidney fibrosis has been recognized as a central pathological feature of chronic kidney disease (CKD) and marked by the excessive deposition of extracellular matrix (ECM). While fibroblast activation is verified as a significant contributing factor to kidney fibrosis, its underlying mechanisms remain to be determined. Increasing evidence suggests that Annexin A1 (ANXA1) is implicated in organ fibrogenesis, but the molecular mechanisms by which it regulates fibroblast activation and renal fibrogenesis remain incompletely elucidated. In this study, we demonstrated that ANXA1 expression was markedly elevated in the interstitial myofibroblasts of fibrotic kidneys from human subjects and rodent models, as well as in renal fibroblasts stimulated with transforming growth factor β1 (TGFβ1). Silencing Anxa1 significantly suppressed TGFβ1-induced fibroblast activation and ECM production. Moreover, silencing Anxa1 in fibroblasts suppressed fibrotic marker expression and alleviated abnormal collagen accumulation in fibrotic renal tissues exposed to unilateral ureteral obstruction (UUO). Mechanistically, ANXA1 interacted with YAP to promote YAP nuclear translocation and activation, ultimately suppressing autophagic flux. Additionally, enhancing autophagic activity with rapamycin improved ECM deposition in UUO-induced fibrotic nephropathy. Collectively, our research suggests that ANXA1 is crucial for renal fibroblast activation and renal fibrogenesis via regulating YAP-mediated autophagy. Targeting ANXA1 may provide a new therapeutic avenue for treating chronic renal disease.