CXC chemokine receptor 7 ameliorates renal fibrosis by inhibiting β-catenin signaling and epithelial-to-mesenchymal transition in tubular epithelial cells

Abstract

Renal fibrosis is a common feature of various chronic kidney diseases. However, the underlying mechanism remains poorly understood. The CXC chemokine receptor (CXCR) family plays a role in renal fibrosis; however, the detailed mechanisms have not been elucidated. In this study, we investigated the potential role of CXCR7 in mediating renal fibrosis. CXCR7 expression is decreased in unilateral ischemia–reperfusion injury (UIRI) and unilateral ureteral obstruction mouse models. Furthermore, CXCR7 was specifically expressed primarily in the Lotus Tetragonolobus Lectin-expressing segment of tubules, was slightly expressed in the peanut agglutinin-expressing segment, and was barely expressed in the Dolichos biflorus agglutinin-expressing segment. Administration of pFlag-CXCR7, an overexpression plasmid for CXCR7, significantly inhibited the activation of β-catenin signaling and protected against the progression of epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a UIRI mouse model. Using cultured HKC-8 cells, we found that CXCR7 significantly downregulated the expression of active β-catenin and fibrosis-related markers, including fibronectin, Collagen I, and α-SMA. Furthermore, CXCR7 significantly attenuated TGF-β1-induced changes in β-catenin signaling, EMT and fibrosis. These results suggest that CXCR7 plays a crucial role in inhibiting the activation of β-catenin signaling and the progression of EMT and renal fibrosis. Thus, CXCR7 could be a novel therapeutic target for renal fibrosis.

Keywords:

• Chronic kidney diseases
• renal fibrosis
• CXCR7
• EMT
• β-catenin

Authors’ contributions

Ping Meng contributed to the conceptualization and methodology of this study and drafted the original manuscript. Chunli Liu and Jingchun Li contributed to the validation and visualization of the data. Ping Fang and Bo Yang contributed to the analysis and interpretation of the data. Yunfang Zhang and Wei Sun contributed to the supervision of the data and the review and editing of the manuscript. All the authors have read and approved the final manuscript.

Disclosure statement

The authors declare that they have no conflict of interest.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors without undue reservation.

Additional information

Funding

This work was supported by the Guangzhou Health Science and Technology project (20221A011115), the National Natural Science Foundation of China (82300760), the Key Medical Discipline of Guangzhou (2021-2023), the Huadu District Basic and Applied Basic Research Joint Funded Project (23HDQYLH01), the Guangzhou Science and Technology project (202102021296) and the Guangdong Medical Research Foundation (A2021251).