title: Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease.
abstract: BACKGROUND
  The major gene mutated in autosomal dominant polycystic kidney disease was first identified over 20 years ago, yet its function remains poorly understood. We have used a systems-based approach to examine the effects of acquired loss of Pkd1 in adult mouse kidney as it transitions from normal to cystic state.
  
  
  METHODS
  We performed transcriptional profiling of a large set of male and female kidneys, along with metabolomics and lipidomics analyses of a subset of male kidneys. We also assessed the effects of a modest diet change on cyst progression in young cystic mice. Fatty acid oxidation and glycolytic rates were measured in five control and mutant pairs of epithelial cells.
  
  
  RESULTS
  We find that females have a significantly less severe kidney phenotype and correlate this protection with differences in lipid metabolism. We show that sex is a major determinant of the transcriptional profile of mouse kidneys and that some of this difference is due to genes involved in lipid metabolism. Pkd1 mutant mice have transcriptional profiles consistent with changes in lipid metabolism and distinct metabolite and complex lipid profiles in kidneys. We also show that cells lacking Pkd1 have an intrinsic fatty acid oxidation defect and that manipulation of lipid content of mouse chow modifies cystic disease.
  
  
  CONCLUSIONS
  Our results suggest PKD could be a disease of altered cellular metabolism.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Menezes
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Cheng-Chao
authors.initials: CC
authors.lastname: Lin
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Germino
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D050396:TRPP Cation Channels
keywords: ADPKD; Autosomal Dominant Polycystic Kidney Disease; Diet; Fatty acid oxidation; Fatty acid oxidation defect; Lipid metabolism; Metabolism; Mouse model; Pkd1; Polycystic kidney disease; Systems biology