Acute kidney injury (AKI) is in high prevalence in the world. However, the therapeutic strategies for AKI are still in mystery. Studies have shown to improve autophagy and lysosomal function could inhibit AKI. But their modulators need to be explored in detail. Annexin A2 (ANXA2) is a phospholipid-binding protein involving in organelle membrane integrity function, suggesting its important role in autophagy and lysosome homeostasis. It implicates ANXA2 potentially protects against AKI. However, this has not been elucidated. Herein, we found that ANXA2 is increased in renal tubules in cisplatin-induced AKI mice. Ectopic expression of ANXA2 improved lysosomal functions and enhanced autophagic flux, further protecting against renal tubular cell apoptosis and kidney injury. Conversely, knockdown of ANXA2 inhibited lysosomal function and autophagy, which aggravated the progression of AKI. Transcriptome sequencing revealed β-catenin signaling is highly responsible for this process. In vitro, we found ANXA2 induced β-catenin activation, further triggering T-cell factor-4 (TCF4)-induced transcription factor EB (TFEB). Furthermore, TFEB promoted lysosome biogenesis to enhance autophagic flux, resulting in the alleviation of AKI. Our new findings underline ANXA2 is a new therapeutic potential for AKI through modulating autophagy and lysosomal function. The underlying mechanism is associated with its inductive effects on β-catenin/TFEB pathway.
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.
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