Wnt/β-catenin/ATF3 signaling promotes the progression from acute kidney injury to chronic kidney disease by regulating mitophagy in mice

Biochem Pharmacol. 2025 Dec;242(Pt 4):117444. doi: 10.1016/j.bcp.2025.117444. Epub 2025 Oct 19.

ABSTRACT

Sustained activation of Wnt/β-catenin signaling has been shown to promote the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). However, its underlying mechanisms remain largely unclear. In this study, we addressed this question using a unilateral ischemia/reperfusion injury model in mice and a hypoxia/reoxygenation model in HKC-8 cells. In vitro, Wnt1 overexpression disrupted mitochondrial structure, increased the expression of DRP1 and p62, and decreased the levels of MFN2, LC3B-II, and Parkin, indicating a shift of mitochondrial dynamics toward fission and impaired mitophagy. In vivo, similar changes were observed, and KP6 treatment partially rescued these defects. RNA sequencing revealed that ATF3 may be associated with the activation of canonical Wnt/β-catenin signaling. ATF3 was expressed in various CKD animal models. Exogenous ATF3 impaired mitochondrial dynamics and mitophagy both in vivo and in vitro, while ATF3 silencing preserved mitochondrial function. Finally, patients with kidney disease exhibited markedly elevated ATF3 levels compared with healthy controls. ATF3 expression correlated positively with serum creatinine, blood urea nitrogen, the extent of renal fibrosis, and the percentage of glomerulosclerosis, and correlated negatively with estimated glomerular filtration rate (eGFR). Collectively, these findings indicate that activation of Wnt/β-catenin/ATF3 signaling facilitates the transition from AKI to CKD by modulating mitochondrial dynamics and mitophagy. ATF3 may serve as a promising potential biomarker for AKI to CKD progression.

PMID:41120013 | DOI:10.1016/j.bcp.2025.117444