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Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.
- Source :
-
EMBO molecular medicine [EMBO Mol Med] 2024 Jun; Vol. 16 (6), pp. 1379-1403. Date of Electronic Publication: 2024 Apr 29. - Publication Year :
- 2024
-
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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Humans
Mice
Disease Progression
Kidney pathology
Kidney metabolism
Oligonucleotides, Antisense pharmacology
Oligonucleotides, Antisense therapeutic use
Aspartate-Ammonia Ligase metabolism
Aspartate-Ammonia Ligase genetics
Aspartate-Ammonia Ligase antagonists & inhibitors
Disease Models, Animal
Polycystic Kidney Diseases metabolism
Polycystic Kidney Diseases drug therapy
Polycystic Kidney Diseases pathology
Polycystic Kidney Diseases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1757-4684
- Volume :
- 16
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- EMBO molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38684863
- Full Text :
- https://doi.org/10.1038/s44321-024-00071-9