PR001585 (Project)

Description:Chronic kidney disease secondary to cystic kidney disease is a leading cause of mortality in patients with tuberous sclerosis complex (TSC) disease. The mechanisms underlying TSC cystic kidney disease are obscure, with no interventions available to prevent cyst formation. Here, we reveal for the first time the misregulated metabolic pathways in TSC kidneys and their relevance to TSC-associated cytogenesis. To this end, we have analyzed the metabolic profile of the whole kidney as well as sorted proximal tubule cell (PTCs) extracts. The metabolomics data show that Tsc1 deletion in nephron progenitor cells changes the arginine biosynthesis pathway as well as a substantial number of metabolic pathways. These changes were associated with overexpression of argininosuccinate synthetase 1 (ASS1), a rate-limiting enzyme in the arginine biosynthetic pathway in TSC KO mice and human kidneys. The rise in ASS1 expression is dependent on mTORC1 activity. Arginine depletion in vitro and in vivo prevented the rise in mTORC1 activity and cell cycle progression and averted the overexpression of previously described cytogenetic signaling proteins, including c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduced the TSC cystic load, indicating the potential therapeutic effects of arginine deprivation as a treatment of TSC-associated kidney disease.