Annexin A13 Protects Against Acute Kidney Injury by Inactivating TGF-β/Smad3 Signaling

Acute kidney injury (AKI) is a common cause of chronic kidney disease, but the underlying pathogenesis remains unclear, and treatment options are limited. Here we report that Annexin A13 (ANXA13), the founder member of Annexins, is renoprotective in AKI. Clinically, ANXA13 is lost in the kidneys of patients with AKI and in mice with ischemic-reperfusion injury (IRI)- or cisplatin-induced AKI. This was associated with reduced serum ANXA13 and elevated urinary ANXA13 levels in the patients. Functionally, ANXA13 overexpression protected against IRI- and cisplatin-induced AKI, whereas ANXA13 silencing promoted AKI. This was further confirmed in renal tubule epithelial cell-specific Anxa13 knockout mice, in which deletion of tubular Anxa13 significantly exacerbated IRI- and cisplatin-induced AKI. Mechanistically, ANXA13 directly binds to the TGF-β Receptor type 1 intracellular domain and inhibits its phosphorylation. This inactivates SMAD3 signaling and blocks Smad3-mediated tubular cell death via p21-dependent G1 cell cycle arrest. Furthermore, our findings revealed that ANXA13 was negatively regulated by TGF-β/SMAD3 signaling, as SMAD3 could bind to the 3'UTR of ANXA13 and inhibit its transcription, which was confirmed in SMAD3 Knockout mice. In conclusion, ANXA13 is renoprotective in AKI and may be a novel therapeutic agent for AKI by targeting TGF-β/SMAD3 signaling.

AKI; ANXA13; TGF‐β receptor type 1; TGF‐β/Smad3.