European journal of pharmacology · 2025
Azathioprine ameliorates cellular senescence in rhabdomyolysis-induced acute kidney injury by inhibiting the Vav1/Rac2/NF-κB pathway in macrophages.
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Su Hongshuang, Liu Qihui, Zhu Lishuang, Sun Keke, Zhang Yan, Yao Congcong, Jiang Feng, Geng Mengke, Paredong Ayinuer, Shou Songtao, Jin Heng
Аннотация
BACKGROUND AND PURPOSE: Rhabdomyolysis (RM) and rhabdomyolysis-induced acute kidney injury (RM-AKI) are increasingly prevalent, yet specific therapies are lacking.Cellular senescence contributes to the transition of RM-AKI to chronic kidney disease (CKD), in which macrophage-tubular epithelial interactions play a pivotal role. Azathioprine, an immunosuppressant, through its metabolite 6-thio-GTP, inhibits Vav1-mediated Rac2 activation; nevertheless, its potential role in RM-AKI has not been elucidated. This study explores the Vav1/Rac2/NF-κB pathway in macrophage-mediated senescence in RM-AKI and azathioprine's efficacy.
EXPERIMENTAL APPROACH: A glycerol-induced RM-AKI mouse model was used. High-throughput RNA sequencing, proteomic profiling, and co-immunoprecipitation were performed to evaluate activation of the Vav1-associated pathway. RAW264.7-TCMK-1 co-cultures verified azathioprine's effects on the pathway and senescence.
KEY RESULTS: RM-AKI mice showed renal senescence (elevated p53, p21, p16, SA-β-gal) and activated macrophage Vav1/Rac2/NF-κB. Azathioprine treatment down-regulated Vav1/Rac2 expression, improved renal function, and mitigated histological injury. In vitro, inhibiting the pathway reduced tubular senescence and improved LaminB1 integrity.
CONCLUSION AND IMPLICATIONS: Activation of macrophage Vav1/Rac2/NF-κB signaling promotes tubular cell senescence, whereas azathioprine counteracts this process by inhibiting the pathway.
EXPERIMENTAL APPROACH: A glycerol-induced RM-AKI mouse model was used. High-throughput RNA sequencing, proteomic profiling, and co-immunoprecipitation were performed to evaluate activation of the Vav1-associated pathway. RAW264.7-TCMK-1 co-cultures verified azathioprine's effects on the pathway and senescence.
KEY RESULTS: RM-AKI mice showed renal senescence (elevated p53, p21, p16, SA-β-gal) and activated macrophage Vav1/Rac2/NF-κB. Azathioprine treatment down-regulated Vav1/Rac2 expression, improved renal function, and mitigated histological injury. In vitro, inhibiting the pathway reduced tubular senescence and improved LaminB1 integrity.
CONCLUSION AND IMPLICATIONS: Activation of macrophage Vav1/Rac2/NF-κB signaling promotes tubular cell senescence, whereas azathioprine counteracts this process by inhibiting the pathway.