Inhibition of Asparagine Synthetase Effectively Retards Polycystic Kidney Disease Progression

Abstract

AbstractPolycystic Kidney Disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustainedin vitroby the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) againstAsnsin orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated withAsns-ASO orScr-ASO revealed major changes in the mutants, several of which are rescued byAsnssilencingin vivo. Indeed, ASNS drives glutamine-dependentde novopyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected byAsns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG withAsns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.