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

Vicki J. Hwang, Jeffrey Kim, Amy Rand, Chaozhe Yang, Steve Sturdivant, Bruce Hammock, P. Darwin Bell, Lisa M. Guay-Woodford, Robert H Weiss

Research output: Contribution to journalArticle

17 Scopus citations


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<sup>cpk/</sup>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.

Original languageEnglish (US)
Pages (from-to)F492-F498
JournalAmerican Journal of Physiology - Renal Physiology
Issue number6
StatePublished - Sep 15 2015



  • Glutamine
  • Metabolomics
  • Oncometabolite
  • Reprogramming

ASJC Scopus subject areas

  • Physiology
  • Urology

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