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

## TL;DR

Annexin A13 protects the kidneys from injury by blocking harmful TGF-β/Smad3 signaling, offering a potential new treatment for acute kidney injury.

## Contribution

This study identifies Annexin A13 as a novel renoprotective factor that inactivates TGF-β/Smad3 signaling in acute kidney injury.

## Key findings

- ANXA13 is lost in the kidneys of patients and mice with acute kidney injury.
- ANXA13 overexpression protects against kidney injury, while its absence worsens it.
- ANXA13 inhibits TGF-β/Smad3 signaling by binding to the TGF-β receptor and blocking phosphorylation.

## Abstract

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 3ʹUTR 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.

ANXA13 is negatively regulated by Smad3 and exerts its protective role in AKI by inactivating TGF‐β/Smad3 signaling and Smad3‐p21 cell cycle arrest pathway through binding to TβRI, inhibiting the interaction between TβRI and TβRII, thereby suppressing TβRI phosporylation.