Arginine Depletion Attenuates Renal Cystogenesis in Tuberous Sclerosis Complex Model

Authors

Athar Amleh
Hadass Pri Chen
Lana Watad
Ifat Abramovich
Bella Agranovich
Eyal Gottlieb
Iddo Z Ben-Dov
Morris Nechama
Oded Volovelsky

Publication Date

6-20-2023

Journal

Cell Reports Medicine

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.

Keywords

Humans, Mice, Animals, Tuberous Sclerosis Complex 2 Protein, Tuberous Sclerosis, Arginine, Mechanistic Target of Rapamycin Complex 1, Kidney

Comments

Supplementary Material

DOI

10.1016/j.xcrm.2023.101073

PMID

37290438

PMCID

PMC10313931

PubMedCentral® Posted Date

June 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes