Inhibition of Axl attenuates acute kidney injury by alleviating inflammation via SOCS3 downregulation in tubular epithelial cells.

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.