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Published on: November 10, 2021
Cxcl10 deficiency attenuates renal interstitial fibrosis through regulating epithelial-to-mesenchymal transition
Jie Gao1, Lingling Wu2, Yinghua Zhao2
1Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Disease, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Fuxing Road 28, Beijing, 100853, China; Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jingwu Road 324, Jinan, 250021, China.
Abstract:
IFN-γ-inducible protein 10 (IP-10, CXCL10) has been widely demonstrated to be involved in multiple kidney pathological processes. However, the role of CXCL10 in renal fibrosis remains unclear. In this study, Cxcl10-deficient (Cxcl10-/-) mice were used to generate the unilateral ureteral obstruction (UUO) model. The level of renal fibrosis and inflammatory cell infiltration was examined in vivo and the effects of CXCL10 on EMT process of HK-2 cells was investigated in vitro. We observed that the injury degree of renal tissue and the collagen deposition levels were lighter and the expression of α-SMA, collagen I and fibronectin was significantly reduced in Cxcl10-/- mice, while the expression of E-cadherin was increased. However, interstitial F4/80-positive macrophages and CD4-positive T lymphocytes were unaffected by knockout of Cxcl10. Furthermore, IFN-γ or CXCL10 stimulation could obviously promote the expression of α-SMA, collagen I, fibronectin and reduce the expression of E-cadherin in HK-2 cells, which could be inhibited by transfection of Cxcl10-siRNA. Our findings suggested Cxcl10 knockout could reduce renal dysfunction and inhibit renal fibrosis through regulating EMT process of renal tubular epithelial cells in murine UUO model. These results may provide a novel insight into the mechanism and a potential therapy target of renal fibrosis.
Insights
Interferon-gamma-inducible protein 10 (IP-10, CXCL10) knockout reduces kidney fibrosis by regulating epithelial-mesenchymal transition. This suggests CXCL10 as a potential therapeutic target for kidney fibrosis.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Interferon-gamma-inducible protein 10 (IP-10, CXCL10) is implicated in kidney diseases.
- The specific role of CXCL10 in renal fibrosis is not fully understood.
Purpose of the Study:
- To investigate the role of CXCL10 in renal fibrosis using a mouse model.
- To explore the effects of CXCL10 on the epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells.
Main Methods:
- Unilateral ureteral obstruction (UUO) model in wild-type and Cxcl10-deficient (Cxcl10-/-) mice.
- Assessment of renal fibrosis, collagen deposition, and inflammatory cell infiltration in vivo.
- In vitro study of CXCL10 effects on HK-2 cells, including EMT markers and siRNA-mediated knockdown.
Main Results:
- Cxcl10-/- mice exhibited reduced renal injury, collagen deposition, and expression of α-SMA, collagen I, and fibronectin, with increased E-cadherin.
- Inflammatory cell infiltration (macrophages, T lymphocytes) was not significantly affected by Cxcl10 knockout.
- IFN-γ or CXCL10 stimulation promoted EMT markers (α-SMA, collagen I, fibronectin) and reduced E-cadherin in HK-2 cells, an effect reversed by Cxcl10-siRNA.
Conclusions:
- Cxcl10 knockout ameliorates renal dysfunction and inhibits renal fibrosis in the UUO model.
- CXCL10 regulates renal fibrosis by modulating the EMT process in renal tubular epithelial cells.
- CXCL10 inhibition represents a potential therapeutic strategy for renal fibrosis.
