Free radical biology & medicine · 2025
Multi-target renal protection in AKI: Exercise-mediated coordination of AMPK energy homeostasis, mTOR autophagy regulation, and NF-κB inflammatory control.
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Wang Xishuai, Li Zhixin, Liu Cong, Du Kangli, Hou Lijia, Zhou Yuehui, Kong Xiliang, Zhao Lunan, Sun Jiakang, Dong Depeng, Zhou Han, Liu Yixuan, Huang Zhenxing, Sun Xiaodi, Li Xiaoyun, Meng Jiale, Wang Ganshen, Wang Yuhan, Sun Shengkun, Song Juncheng, Nan Bingxu, Xu Haoyue, Miao Jiasen, Zhao Zihao, Zhao Qi, An Yuheng, Feng Yue, Zhou Fangmin
Аннотация
BACKGROUND: Aerobic exercise (AE) confers protection against acute kidney injury (AKI), but mechanisms remain incompletely elucidated. We investigated how AE preconditioning protects against sepsis-induced AKI through transcriptomic reprogramming, inflammatory regulation, autophagy modulation, and metabolic adaptation.
METHODS: Mice were subjected to 4-week AE before AKI induction. We quantified renal function biomarkers, oxidative stress markers, cytokines, and metabolic parameters, performed transcriptomic analysis, and validated mechanisms using mTOR agonist MHY1485.
RESULTS: AE preconditioning significantly increased survival rates and attenuated AKI by reducing inflammatory and oxidative damage. It significantly improved the renal dysfunction marker (blood urea nitrogen, creatinine, uric acid, and glomerular filtration rate) levels and improved metabolism by increasing the ATP/ADP ratio, NAD+/NADH ratio, and phosphocreatine level and decreasing lactate accumulation. Transcriptomic profiling revealed substantial gene expression alterations in the LPS-induced AKI group (ALI vs. Con groups), with 3595 differentially expressed genes (DEGs) that were enriched in AMPK, mTORC1, NF-κB, and TNF pathways. However, AE preconditioning induced transcriptomic reprogramming characterized by 392 DEGs (ALI vs. AE + ALI groups), which were significantly enriched in AMPK, mTORC1 and NF-κB signaling pathways. Exercise ameliorated AKI through three synergistic mechanisms: (1) AMPK activation restored energy homeostasis by enhancing PGC-1α-mediated mitochondrial biogenesis and PPARα/CPT1a-driven fatty acid oxidation; (2) mTORC1 activation suppressed excessive autophagy via ULK1-ATG13-FIP200 complex inhibition; and (3) NF-κB inhibition was achieved through dual suppression of IL-1R1/TAK1 and TLR3/MyD88 pathways, reducing pro-inflammatory cytokines. Notably, mTOR activation by MHY1485 markedly increased survival rates, attenuated renal injury, promoted energy metabolism, and suppressed excessive autophagy.
CONCLUSIONS: AE exerts multi-target nephroprotection in AKI by regulating AMPK-mediated metabolic reprogramming, mTOR-dependent autophagy control, and NF-κB inflammatory suppression. This study delineate the molecular basis of exercise-induced renal protection and identifies mTOR as a potential therapeutic target for AKI.
METHODS: Mice were subjected to 4-week AE before AKI induction. We quantified renal function biomarkers, oxidative stress markers, cytokines, and metabolic parameters, performed transcriptomic analysis, and validated mechanisms using mTOR agonist MHY1485.
RESULTS: AE preconditioning significantly increased survival rates and attenuated AKI by reducing inflammatory and oxidative damage. It significantly improved the renal dysfunction marker (blood urea nitrogen, creatinine, uric acid, and glomerular filtration rate) levels and improved metabolism by increasing the ATP/ADP ratio, NAD+/NADH ratio, and phosphocreatine level and decreasing lactate accumulation. Transcriptomic profiling revealed substantial gene expression alterations in the LPS-induced AKI group (ALI vs. Con groups), with 3595 differentially expressed genes (DEGs) that were enriched in AMPK, mTORC1, NF-κB, and TNF pathways. However, AE preconditioning induced transcriptomic reprogramming characterized by 392 DEGs (ALI vs. AE + ALI groups), which were significantly enriched in AMPK, mTORC1 and NF-κB signaling pathways. Exercise ameliorated AKI through three synergistic mechanisms: (1) AMPK activation restored energy homeostasis by enhancing PGC-1α-mediated mitochondrial biogenesis and PPARα/CPT1a-driven fatty acid oxidation; (2) mTORC1 activation suppressed excessive autophagy via ULK1-ATG13-FIP200 complex inhibition; and (3) NF-κB inhibition was achieved through dual suppression of IL-1R1/TAK1 and TLR3/MyD88 pathways, reducing pro-inflammatory cytokines. Notably, mTOR activation by MHY1485 markedly increased survival rates, attenuated renal injury, promoted energy metabolism, and suppressed excessive autophagy.
CONCLUSIONS: AE exerts multi-target nephroprotection in AKI by regulating AMPK-mediated metabolic reprogramming, mTOR-dependent autophagy control, and NF-κB inflammatory suppression. This study delineate the molecular basis of exercise-induced renal protection and identifies mTOR as a potential therapeutic target for AKI.