#1771 ANXA13 protects against acute kidney injury by inhibiting TGF-β/Smad3 pathway

Abstract

Abstract Background and Aims Acute kidney injury (AKI) is a common clinical syndrome characterized by rapid loss of kidney function but with limited diagnostic and treatment options. Annexins (ANXA) are a superfamily of calcium-dependent and lipid-binding proteins involved in multiple intracellular and extracellular functions. As a founding member of ANXA, ANXA13 is considered the prototype of a conserved evolutionary property of the annexin superfamily and is restricted to kidney and intestinal epithelial cells. However, it is currently unclear whether ANXA13 is a key regulator of AKI. Therefore, we aimed to investigate the role of ANXA13 in AKI. Method Kidney biopsy tissues from AKI patients were collected for immunohistochemical examination and ELISA method was used to detect the concentration of ANXA13 in serum and urine. A mouse model of AKI induced by ischemia-reperfusion injury (IRI) was established to verify the role of ANXA13 in AKI. RNA sequencing was also used to explore the mechanism of ANXA13 in AKI, and this result was further confirmed using Smad3 wild-type (WT) and knockout (KO) mice. Results AKI patients had reduced serum ANXA13 levels and increased urinary ANXA13 levels compared with healthy controls. The levels of ANXA13 in both serum and urine are related to serum creatinine (Scr). In kidney tissue, ANXA13 was significantly reduced in both AKI patients and IRI-AKI mice. By overexpressing ANXA13 by specifically transferring ANXA13-expressing plasmid into IRI-AKI mice via ultrasound microbubble-mediated kidney, we found that ANXA13 reduced Scr and blood urea nitrogen (BUN) levels and renal function in IRI-AKI mice. damage. In contrast, knockdown of ANXA13 by shANXA13 plasmid significantly exacerbated renal injury. Mechanistically, we found that the protective mechanism of ANXA13 was related to the inhibition of the TGF-β/Smad3-p21 cell cycle arrest pathway, and the aggravating effect of shANXA13 was reversed in Smad3 knockout mice. In turn, activation of Smad3 also suppresses ANXA13 mRNA and protein levels in vivo and in vitro. Conclusion ANXA13 can intervene in AKI by inhibiting the TGF-β/Smad3-p21 cell cycle blocking pathway. In turn, activation of Smad3 inhibits ANXA13 expression. Therefore, ANXA13 may be a new therapeutic target for AKI.