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 pathogenic mechanisms remain unclear and treatments remain limited. Here we report that Annexin A13 (ANXA13), the founder member of Annexins is renal protective in AKI. Clinically, ANXA13 was lost in the AKI kidney in both patients and ischemic-reperfusion injury (IRI)-induced mice. This was associated with declined serum levels of ANXA13 but elevated urinary ANXA13. To explore the functional role of ANXA13 in AKI, we kidney-specifically overexpressed ANXA13 and found that overexpressing ANXA13 protected against IRI-AKI by significantly inhibiting tubular necrosis and lowering serum creatinine. In contrast, kidney-specifically silencing ANXA13 largely promoted AKI. Mechanistically, renal ANXA13 was downregulated by TGF-β1 via Smad3 signaling as mice lacking Smad3 were protected from the loss of renal ANXA13 and the development of AKI. More importantly, we also uncovered that ANXA13 could directly bind TGF-β receptor type 1 and inhibit its phosphorylation, thereby inactivating Smad3 signaling and Smad3-mediated tubular cell death via the p21-dependent G1cell cycle arrest. In conclusion, ANXA13 is renal protective and may be a potential new biomarker and a novel therapeutic agent for AKI.