Annexin A2 plays a key role in protecting against acute kidney injury through β-catenin/TFEB pathway

Abstract

Aim Acute kidney injury (AKI) is becoming a heavy health burden worldwide. There are no effective therapeutic strategies nowadays. Recent studies showed that autophagy and lysosome stabilization could inhibit tubular cell apoptosis, and protect against AKI. Annexin A2 (ANXA2), a calcium-regulated phospholipid-binding protein, was found to be highly involved in autophagy. However, its role in AKI has not been elucidated. Results We found that ANXA2 is highly increased in renal tubular cells in cisplatin-treated mice, and in the urine and kidney samples from AKI patients. Ectopic expression of ANXA2 promoted lysosomal functions and autophagic flux, and protected against tubular cell apoptosis in AKI mice. Transcriptome analysis further identified that ANXA2 was intimately correlated with lysosome biogenesis, autophagy, and β-catenin signaling. Mechanistically, ANXA2 induced β-catenin activation through binding to and inhibiting on GSK3β, which further triggered T cell factor 4 (TCF4)-mediated transcription factor EB (TFEB) signaling pathway. As a result, TFEB activation regulated lysosomal proteostasis and effectively promoted autophagic flux. This greatly protected against renal tubular cell apoptosis and alleviated AKI. Innovation: These findings underline ANXA2 serves as a new therapeutic potential for AKI which lacks effective treatment. Conclusion We demonstrated that ANXA2 plays a key role in retarding AKI, which is associated with its inductive effects on β-catenin/TFEB-induced lysosmal pathway.