Abstract
Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in mice, indicating the potential therapeutic effects of arginine deprivation for the treatment of TSC-associated kidney disease.
Original language | English (US) |
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Article number | 101073 |
Journal | Cell Reports Medicine |
Volume | 4 |
Issue number | 6 |
DOIs | |
State | Published - Jun 20 2023 |
Externally published | Yes |
Keywords
- ASS1
- PTCs
- TSC
- arginine metabolism
- argininosuccinate synthetase 1
- cystogenesis
- mTORC1
- mechanistic target of rapamycin complex 1
- proximal tubule cells
- tuberous sclerosis complex
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology