Brain-derived Extracellular Vesicles CircUsp32 Polarized Macrophages Causing Acute Kidney Injury After Traumatic Brain Injury

Science advances  ·  2025

Jiayuanyuan Fu; Jingheng Wu; Mengran Du; Xu Wang; Qi Shi; Yehong Fang; Yu Lan; Qiaoli Wu; Guobin Zhang; Lixia Xu; Hua Yan;

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ABSTRACT

Brain-kidney cross-talk following traumatic brain injury (TBI) can induce acute kidney injury (AKI), but mechanisms remain unclear. Extracellular vesicles derived from injured brain tissue (TBI-EVs) may mediate brain-kidney interactions. In vivo experiments demonstrated that TBI-EVs causes AKI by promoting pro-inflammatory macrophage polarization. TBI-EVs markedly increased AKI markers and proportion of pro-inflammatory-polarized macrophages. Mechanistically, transcriptomics of TBI-EVs revealed high circUsp32 expression. Subsequent in vitro assays showed that circUsp32 competitively binds to the SH2 domain of suppressor of cytokine signaling 1 (Socs1), affecting interferon regulator factor 7 (IRF7) ubiquitination and promoting pro-inflammatory polarization. CircUsp32 knockdown reduced pro-inflammatory polarization and alleviated AKI in TBI mice. In addition, circUsp32 is homologous to hsa_circ_0044940, which may serve as a predicted biomarker of AKI after TBI. Notably, AKI following TBI may contribute to neuroinflammation via uremic toxins. Collectively, these findings suggest that circUsp32 mediates macrophage polarization through the Socs1/IRF7 axis and could be a potential biomarker for AKI following TBI.

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