title: Dysregulation of the glutamine transporter Slc38a3 (SNAT3) and ammoniagenic enzymes in obese, glucose-intolerant mice.
abstract: OBJECTIVE
  Uric acid nephrolithiasis is prevalent among patients with type 2 diabetes and metabolic syndrome; it is correlated with an acidic urine and lower urinary ammonium excretion and is likely associated with insulin resistance. Insulin stimulates ammoniagenesis in renal cell lines via increased phosphate-dependent glutaminase (PDG) activity and glutamine metabolism. Ammonium excretion into the proximal tubule is mediated at least in part by the Na(+)/H(+)-exchanger NHE3 and in the collecting duct involving the Rhesus protein RhCG. Here we tested, whether obesity and insulin resistance in a diet-induced mouse model could contribute to deranged ammonium excretion.
  
  
  METHODS
  Obesity was induced by diet in mice and the impact on key molecules of proximal tubular ammoniagenesis and urinary acid excretion tested.
  
  
  RESULTS
  Diet-induced obesity was confirmed by pathological intraperitoneal glucose tolerance tests (IPGTT). Three groups of mice were compared: control mice; obese, glucose-intolerant with abnormal IPGTT (O-GI); or moderate weight with normal IPGTT (Non-Responders, NR). Basal urinary ammonium excretion did not differ among groups. However, acid loading increased urinary ammonium excretion in all groups, but to a lesser extent in the O-GI group. SNAT3 mRNA expression was enhanced in both obese groups. PDG expression was elevated only in acid-loaded O-GI mice, whereas PEPCK was enhanced in both O-GI and NR groups given NH4CI. NHE activity in the brush border membrane of the proximal tubule was strongly reduced in the O-GI group whereas RhCG expression was similar.
  
  
  CONCLUSIONS
  In sum, obesity and glucose intolerance impairs renal ammonium excretion in response to NH4CI feeding most likely through reduced NHE activity. The stimulation of SNAT3 and ammoniagenic enzyme expression may be compensatory but futile.
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology ZIHP, University of Zurich, Zurich, Switzerland.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Busque
authors.forename: Gerti
authors.initials: G
authors.lastname: Stange
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism*; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D005951:Glucose Tolerance Test; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C403222:system N protein 1; D000641:Ammonia