title: Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease.
abstract: BACKGROUND
  Advanced chronic kidney disease (CKD) is associated with the development of renal metabolic acidosis. Metabolic acidosis per se may represent a trigger for progression of CKD. Renal acidosis of CKD is characterized by low urinary ammonium excretion with preserved urinary acidification indicating a defect in renal ammoniagenesis, ammonia excretion or both. The underlying molecular mechanisms, however, have not been addressed to date.
  
  
  METHODS
  We examined the Han:SPRD rat model and used a combination of metabolic studies, mRNA and protein analysis of renal molecules involved in acid-base handling.
  
  
  RESULTS
  We demonstrate that rats with reduced kidney function as evident from lower creatinine clearance, lower haematocrit, higher plasma blood urea nitrogen, creatinine, phosphate and potassium had metabolic acidosis that could be aggravated by HCl acid loading. Urinary ammonium excretion was highly reduced whereas urinary pH was more acidic in CKD compared with control animals. The abundance of key enzymes and transporters of proximal tubular ammoniagenesis (phosphate-dependent glutaminase, PEPCK and SNAT3) and bicarbonate transport (NBCe1) was reduced in CKD compared with control animals. In the collecting duct, normal expression of the B1 H(+)-ATPase subunit is in agreement with low urinary pH. In contrast, the RhCG ammonia transporter, critical for the final secretion of ammonia into urine was strongly down-regulated in CKD animals.
  
  
  CONCLUSIONS
  In the Han:SPRD rat model for CKD, key molecules required for renal ammoniagenesis and ammonia excretion are highly down-regulated providing a possible molecular explanation for the development and maintenance of renal acidosis in CKD patients.
authors.affiliation: Institute of Physiology and ZIHP, University of Zurich, Zurich, Switzerland.
authors.forename: Remy
authors.initials: R
authors.lastname: Bürki
authors.affiliation: Institute of Physiology and ZIHP, University of Zurich, Zurich, Switzerland Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.affiliation: Institute of Physiology and ZIHP, University of Zurich, Zurich, Switzerland.
authors.forename: Carla
authors.initials: C
authors.lastname: Bettoni
authors.affiliation: Division of Nephrology, University Hospital Zurich, Zurich, Switzerland Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xueqi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Serra
authors.affiliation: Institute of Physiology and ZIHP, University of Zurich, Zurich, Switzerland.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D000138:Acidosis / Q000235:genetics*; D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates / Q000737:chemistry; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005972:Glutaminase / Q000378:metabolism; D006579:Heterozygote; D006863:Hydrogen-Ion Concentration; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D010710:Phosphates / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism* / Q000652:urine*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D001639:Bicarbonates; D047908:Intracellular Signaling Peptides and Proteins; D010710:Phosphates; D012333:RNA, Messenger; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C403222:system N protein 1; D000641:Ammonia; D003404:Creatinine; D005972:Glutaminase; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP)
keywords: CKD; acidosis; ammoniagenesis