International immunopharmacology · 2025
Maladaptive autophagy mediates renal fibrosis under caloric restriction in aristolochic acid nephropathy.
СтатьяНазвание и аннотация: Перевод в очереди
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Yan Ziyu, Yue Ruchi, Wang Hongtao, Zha Hongchu, Xia Yao, Huang Hua, Li Huimin, Shi Lang, Zhu Jiefu, Li Chenglong, Ding Mao, Song Zhixia
Аннотация
BACKGROUND: Caloric restriction (CR) is widely promoted for systemic health benefits, yet its impact on toxin-induced nephropathy remains uncertain. We investigated whether CR modifies injury and repair in aristolochic acid (AA) nephropathy and delineated the underlying mechanism.
METHODS: Male C57BL/6J mice were subjected to AA-induced nephropathy and assigned to ad libitum (AL) or CR diets initiated after injury. Renal function, histology and fibrosis markers were quantified. CAG-RFP-GFP-LC3 reporter mice were used for in vivo autophagy flux imaging. Rapamycin (mTORC1 inhibition) and 3-MA (autophagy inhibition) were used pharmacologically; tubule-specific Atg7 knockout tested the requirement of autophagy genetically.
RESULTS: Compared with AL, CR aggravated AA-induced renal dysfunction and tubulointerstitial fibrosis. CR sustained autophagy alongside mTORC1 suppression and reduced p-ULK1. Rapamycin phenocopied the CR effects on flux and signaling, whereas 3-MA reversed them. Atg7 deletion in tubular epithelium mitigated CR-aggravated injury and fibrosis in vivo. The CR-like in vitro setting reproduced heightened autophagy and increased injury readouts under AA.
CONCLUSIONS: In AA nephropathy, post-injury CR diverts repair from regeneration to maladaptive fibrosis by sustaining high-amplitude autophagy and suppressing mTORC1-dependent repair.
METHODS: Male C57BL/6J mice were subjected to AA-induced nephropathy and assigned to ad libitum (AL) or CR diets initiated after injury. Renal function, histology and fibrosis markers were quantified. CAG-RFP-GFP-LC3 reporter mice were used for in vivo autophagy flux imaging. Rapamycin (mTORC1 inhibition) and 3-MA (autophagy inhibition) were used pharmacologically; tubule-specific Atg7 knockout tested the requirement of autophagy genetically.
RESULTS: Compared with AL, CR aggravated AA-induced renal dysfunction and tubulointerstitial fibrosis. CR sustained autophagy alongside mTORC1 suppression and reduced p-ULK1. Rapamycin phenocopied the CR effects on flux and signaling, whereas 3-MA reversed them. Atg7 deletion in tubular epithelium mitigated CR-aggravated injury and fibrosis in vivo. The CR-like in vitro setting reproduced heightened autophagy and increased injury readouts under AA.
CONCLUSIONS: In AA nephropathy, post-injury CR diverts repair from regeneration to maladaptive fibrosis by sustaining high-amplitude autophagy and suppressing mTORC1-dependent repair.