Inhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cells
Abstract Background In acute kidney injury (AKI), inflammatory crosstalk between tubular epithelial cells (TECs) and immune cells drives disease progression. Although the Axl-SOCS3 axis in myeloid cells typically suppresses inflammation, TEC-specific SOCS3 deletion paradoxically protects against AKI...
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| Format: | Article |
| Language: | English |
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BMC
2025-07-01
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| Series: | BMC Nephrology |
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| Online Access: | https://doi.org/10.1186/s12882-025-04222-z |
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| _version_ | 1849238862031749120 |
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| author | Xin Kang Qiuhua Gu Xi Cheng Junya Jia Tiekun Yan |
| author_facet | Xin Kang Qiuhua Gu Xi Cheng Junya Jia Tiekun Yan |
| author_sort | Xin Kang |
| collection | DOAJ |
| description | Abstract Background In acute kidney injury (AKI), inflammatory crosstalk between tubular epithelial cells (TECs) and immune cells drives disease progression. Although the Axl-SOCS3 axis in myeloid cells typically suppresses inflammation, TEC-specific SOCS3 deletion paradoxically protects against AKI, suggesting a cell type-specific pro-inflammatory role. Methods We induced AKI via bilateral ischemia/reperfusion (IRI) in mice. The Axl-specific pharmacological inhibitor R428 was administered via subcutaneous injection immediately post-IRI, with plasma and kidney samples collected 24 h later. To assess the effects of SOCS3 in TECs, small interfering RNA was used to silence SOCS3 in cisplatin injured HK2 cells. Axl/SOCS3 expression levels were assessed in human AKI biopsies. Results In AKI patients and IRI mice, Axl was upregulated in interstitial immune cells, while SOCS3 increased in TECs. Axl inhibition by R428 attenuated renal injury, reducing inflammatory infiltration, NF-κB p65 phosphorylation, and TEC SOCS3 expression. Notably, SOCS3 knockdown in TECs suppressed NF-κB activation and IL-1β/IL-6 production, implicating Axl-SOCS3 as a pro-inflammatory amplifier in AKI. Conclusion The Axl-SOCS3 axis exacerbates AKI by reinforcing NF-κB-driven inflammation in TECs, creating a vicious cycle between immune cells and TECs. Targeting this cross-cellular pro-inflammatory pathway offers a promising therapeutic strategy for AKI. |
| format | Article |
| id | doaj-art-72d8bf0b71a74745b85ece2da2d985d2 |
| institution | Kabale University |
| issn | 1471-2369 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Nephrology |
| spelling | doaj-art-72d8bf0b71a74745b85ece2da2d985d22025-08-20T04:01:23ZengBMCBMC Nephrology1471-23692025-07-0126111110.1186/s12882-025-04222-zInhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cellsXin Kang0Qiuhua Gu1Xi Cheng2Junya Jia3Tiekun Yan4Department of Nephrology, General Hospital of Tianjin Medical UniversityDepartment of Nephrology, General Hospital of Tianjin Medical UniversityDepartment of Nephrology, General Hospital of Tianjin Medical UniversityDepartment of Nephrology, General Hospital of Tianjin Medical UniversityDepartment of Nephrology, General Hospital of Tianjin Medical UniversityAbstract Background In acute kidney injury (AKI), inflammatory crosstalk between tubular epithelial cells (TECs) and immune cells drives disease progression. Although the Axl-SOCS3 axis in myeloid cells typically suppresses inflammation, TEC-specific SOCS3 deletion paradoxically protects against AKI, suggesting a cell type-specific pro-inflammatory role. Methods We induced AKI via bilateral ischemia/reperfusion (IRI) in mice. The Axl-specific pharmacological inhibitor R428 was administered via subcutaneous injection immediately post-IRI, with plasma and kidney samples collected 24 h later. To assess the effects of SOCS3 in TECs, small interfering RNA was used to silence SOCS3 in cisplatin injured HK2 cells. Axl/SOCS3 expression levels were assessed in human AKI biopsies. Results In AKI patients and IRI mice, Axl was upregulated in interstitial immune cells, while SOCS3 increased in TECs. Axl inhibition by R428 attenuated renal injury, reducing inflammatory infiltration, NF-κB p65 phosphorylation, and TEC SOCS3 expression. Notably, SOCS3 knockdown in TECs suppressed NF-κB activation and IL-1β/IL-6 production, implicating Axl-SOCS3 as a pro-inflammatory amplifier in AKI. Conclusion The Axl-SOCS3 axis exacerbates AKI by reinforcing NF-κB-driven inflammation in TECs, creating a vicious cycle between immune cells and TECs. Targeting this cross-cellular pro-inflammatory pathway offers a promising therapeutic strategy for AKI.https://doi.org/10.1186/s12882-025-04222-zAcute kidney injuryInflammationTubular epithelial cellsAxlSuppressor of cytokine signaling 3 |
| spellingShingle | Xin Kang Qiuhua Gu Xi Cheng Junya Jia Tiekun Yan Inhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cells BMC Nephrology Acute kidney injury Inflammation Tubular epithelial cells Axl Suppressor of cytokine signaling 3 |
| title | Inhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cells |
| title_full | Inhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cells |
| title_fullStr | Inhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cells |
| title_full_unstemmed | Inhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cells |
| title_short | Inhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cells |
| title_sort | inhibition of axl attenuates acute kidney injury by alleviating inflammation via socs3 downregulation in tubular epithelial cells |
| topic | Acute kidney injury Inflammation Tubular epithelial cells Axl Suppressor of cytokine signaling 3 |
| url | https://doi.org/10.1186/s12882-025-04222-z |
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