Lkb1 deficiency confers glutamine dependency in polycystic kidney disease

Ebony M. Flowers, Jessica Sudderth, Lauren Zacharias, Glenda Mernaugh, Roy Zent, Ralph J. Deberardinis, Thomas J. Carroll

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Several studies reported that the serine-threonine kinase Lkb1 is dysregulated in PKD. Here we show that genetic ablation of Lkb1 in the embryonic ureteric bud has no effects on tubule formation, maintenance, or growth. However, co-ablation of Lkb1 and Tsc1, an mTOR repressor, results in an early developing, aggressive form of PKD. We find that both loss of Lkb1 and loss of Pkd1 render cells dependent on glutamine for growth. Metabolomics analysis suggests that Lkb1 mutant kidneys require glutamine for non-essential amino acid and glutathione metabolism. Inhibition of glutamine metabolism in both Lkb1/Tsc1 and Pkd1 mutant mice significantly reduces cyst progression. Thus, we identify a role for Lkb1 in glutamine metabolism within the kidney epithelia and suggest that drugs targeting glutamine metabolism may help reduce cyst number and/or size in PKD.

Original languageEnglish (US)
Article number814
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

kidney diseases
glutamine
Polycystic Kidney Diseases
Glutamine
metabolism
Metabolism
cysts
kidneys
Ablation
Kidney
ablation
Cysts
Growth
Cyst Fluid
Enzyme inhibition
Inborn Genetic Diseases
glutathione
Metabolomics
epithelium
Protein-Serine-Threonine Kinases

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. / Flowers, Ebony M.; Sudderth, Jessica; Zacharias, Lauren; Mernaugh, Glenda; Zent, Roy; Deberardinis, Ralph J.; Carroll, Thomas J.

In: Nature Communications, Vol. 9, No. 1, 814, 01.12.2018.

Research output: Contribution to journalArticle

Flowers, Ebony M. ; Sudderth, Jessica ; Zacharias, Lauren ; Mernaugh, Glenda ; Zent, Roy ; Deberardinis, Ralph J. ; Carroll, Thomas J. / Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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