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Am J Physiol Renal Physiol. 2015 Sep 15;309(6):F492-8. doi: 10.1152/ajprenal.00238.2015. Epub 2015 Jul 8.

The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate.

Author information

1
Graduate Group in Integrative Genetics and Genomics, University of California, Davis, California; Division of Nephrology, Department of Internal Medicine, University of California, Davis, California;
2
Division of Nephrology, Department of Internal Medicine, University of California, Davis, California;
3
Department of Entomology, University of California, Davis, California;
4
Center for Translational Science, Children's National Health System, Washington, District of Columbia;
5
Metabolon, Durham, North Carolina;
6
Department of Entomology, University of California, Davis, California; Cancer Center, University of California, Davis, California;
7
Division of Nephrology, Department of Medicine, Medical University of South Carolina and Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
8
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.

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.

KEYWORDS:

ARPKD; glutamine; metabolomics; oncometabolite; reprogramming

PMID:
26155843
PMCID:
PMC4572393
DOI:
10.1152/ajprenal.00238.2015
[Indexed for MEDLINE]
Free PMC Article

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