Targeting WNT5A Noncanonical Signaling Attenuates Renal Fibrosis Progression in Acute Kidney Injury

Sijie Gu; Haoran Feng; Xiaomei Li; Yang Dong; Yonglin Peng; Qiye Liu; Xuhao Zhang; Jiayin You; Jinwei Zhu; Xiaodong Zhao; Xizhi Guo; Niansong Wang; Ying Fan

doi:10.1016/j.ymthe.2025.06.039

Targeting WNT5A Noncanonical Signaling Attenuates Renal Fibrosis Progression in Acute Kidney Injury

Mol Ther. 2025 Jun 27:S1525-0016(25)00490-3. doi: 10.1016/j.ymthe.2025.06.039. Online ahead of print.

Authors

Sijie Gu¹, Haoran Feng¹, Xiaomei Li¹, Yang Dong¹, Yonglin Peng², Qiye Liu¹, Xuhao Zhang³, Jiayin You¹, Jinwei Zhu⁴, Xiaodong Zhao², Xizhi Guo⁵, Niansong Wang⁶, Ying Fan⁷

Affiliations

¹ Department of Nephrology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road. Shanghai, 200233, China.
² Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Jiao Tong University, 800 Dongchuan Road. Shanghai, 200240, China.
³ Shanghai Starriver Bilingual School, 2588 Jindu Road. Shanghai, 201100, China.
⁴ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, 800 Dongchuan Road. Shanghai, 200240, China.
⁵ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, 800 Dongchuan Road. Shanghai, 200240, China. Electronic address: xzguo2005@sjtu.edu.cn.
⁶ Department of Nephrology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road. Shanghai, 200233, China. Electronic address: wangniansong2012@163.com.
⁷ Department of Nephrology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road. Shanghai, 200233, China. Electronic address: fanying@shsmu.edu.cn.

PMID: 40581819
DOI: 10.1016/j.ymthe.2025.06.039

Abstract

Preventing progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the AKI-to-CKD transition and its underlying mechanisms. Renal biopsies from patients with AKI showed marked upregulation of WNT5A and its receptor CD146 in proximal tubules, with higher expression in patients with CKD progression. In murine AKI models, Wnt5a knockdown attenuated CKD progression. Conversely, proximal tubular overexpression of Wnt5a exacerbated renal fibrosis in ischemia-reperfusion injury (IRI) mice, which was alleviated by Box5, a specific WNT5A antagonist. In vitro, WNT5A overexpression in TGF-β-stimulated HK-2 cells promoted CD146 upregulation, activated JNK phosphorylation, and enhanced SNAI1 expression. The genetic silencing of WNT5A/CD146 and JNK inhibition suppresses SNAI1 expression and attenuates fibrotic responses. Mechanistically, JNK-mediated c-JUN phosphorylation promoted its interaction with KLF5 at the SNAI1 promoter, driving renal fibrosis. Elevated serum levels of soluble CD146 correlated with renal function in patients with AKI and were higher in patients exhibiting CKD progression. Inhibition of WNT5A could serve as a therapeutic target for delaying renal fibrosis in AKI progression.