Maladaptive autophagy mediates renal fibrosis under caloric restriction in aristolochic acid nephropathy
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Published on: November 7, 2017
Ziyu Yan1, Ruchi Yue2, Hongtao Wang1
1Departiment of Nephrology, The First clinical Medical College of China Three Gorges University, Center People's Hospital of Yichang, Yichang, Hubei 443000, China; Institute of kidney disease, China Three Gorges University, Yichang, Hubei 443000, China; Medical college of China three gorges University, Yichang, Hubei 443000, China.
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.
