title: The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate.
abstract: Since polycystic kidney disease (PKD) was first noted over 30 years ago to have neoplastic parallels, there has been a resurgent interest in elucidating neoplasia-relevant pathways in PKD. Taking a nontargeted metabolomics approach in the B6(Cg)-Cys1(cpk/)J (cpk) mouse model of recessive PKD, we have now characterized metabolic reprogramming in these tissues, leading to a glutamine-dependent TCA cycle shunt toward total 2-hydroxyglutarate (2-HG) production in cpk compared with B6 wild-type kidney tissue. After confirmation of increased 2-HG expression in immortalized collecting duct cpk cells as well as in human autosomal recessive PKD tissue using targeted analysis, we show that the increase in 2-HG is likely due to glutamine-sourced α-ketoglutarate. In addition, cpk cells require exogenous glutamine for growth such that inhibition of glutaminase-1 decreases cell viability as well as proliferation. This study is a demonstration of the striking parallels between recessive PKD and cancer metabolism. Our data, once confirmed in other PKD models, suggest that future therapeutic approaches targeting this pathway, such as using glutaminase inhibitors, have the potential to open novel treatment options for renal cystic disease.
authors.affiliation: Graduate Group in Integrative Genetics and Genomics, University of California, Davis, California; Division of Nephrology, Department of Internal Medicine, University of California, Davis, California;
authors.forename: Vicki J
authors.initials: VJ
authors.lastname: Hwang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of California, Davis, California;
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Entomology, University of California, Davis, California;
authors.forename: Amy
authors.initials: A
authors.lastname: Rand
authors.affiliation: Center for Translational Science, Children's National Health System, Washington, District of Columbia;
authors.forename: Chaozhe
authors.initials: C
authors.lastname: Yang
authors.affiliation: Metabolon, Durham, North Carolina;
authors.forename: Steve
authors.initials: S
authors.lastname: Sturdivant
authors.affiliation: Department of Entomology, University of California, Davis, California; Cancer Center, University of California, Davis, California;
authors.forename: Bruce
authors.initials: B
authors.lastname: Hammock
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina and Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
authors.affiliation: Center for Translational Science, Children's National Health System, Washington, District of Columbia;
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.affiliation: Graduate Group in Integrative Genetics and Genomics, University of California, Davis, California; Division of Nephrology, Department of Internal Medicine, University of California, Davis, California; Cancer Center, University of California, Davis, California; Medical Service, Sacramento Veterans Affairs Medical Center, Sacramento, California rhweiss@ucdavis.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005972:Glutaminase / Q000037:antagonists & inhibitors; D005973:Glutamine / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D055432:Metabolomics; D051379:Mice; D008957:Models, Genetic; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D005977:Glutarates; D005973:Glutamine; C019417:alpha-hydroxyglutarate; D003402:Creatine Kinase; D005972:Glutaminase
keywords: ARPKD; glutamine; metabolomics; oncometabolite; reprogramming