ArticleEMBO molecular medicine2024
Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.
Article in EMBO molecular medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Glutamine metabolism in health and disease.Signal transduction and targeted therapy · 2026Review
- Modeling Complex Developmental Disease: The Case of Polycystic Kidney Disease.Journal of developmental biology · 2026Review
- Amino acid homeostasis in the kidney: Physiological roles and pathological dysregulation.Physiological reports · 2026Review
- Purine-Metabolism Reprogramming Associated with Failed-Repair Proximal Tubule States in the AKI-to-CKD Transition.Metabolites · 2026Article
- Design of Nanocarriers for Kidney Targeted Delivery of Nucleic Acid Therapeutics.Macromolecular bioscience · 2026Review
- The Renal Micro-RNA Expression Profile of Pkd1RC/RC Mice Changes Longitudinally with the Progression of the Disease.Kidney360 · 2026Article
- Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies.EMBO molecular medicine · 2025Review
- RNA-Based Therapies in Kidney Diseases.Journal of inflammation research · 2025Review
- Targeting Metabolic Reprogramming in Polycystic Kidney Disease.Journal of the American Society of Nephrology : JASN · 2024Article
Corrections and comments
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Authors and funding
17 authors.
Funding
Abstract
Polycystic 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, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in 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 with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.