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.

CONCLUSION:

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: Remy Bürki, Nilufar Mohebbi, Carla Bettoni, Xueqi Wang, Andreas L Serra, Carsten A Wagner
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 30 Issue 5 Pg. 770-81 (May 2015) ISSN: 1460-2385 [Electronic] England
• PMID: 25523450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Chemical References

• Amino Acid Transport Systems, Neutral
• Bicarbonates
• Intracellular Signaling Peptides and Proteins
• Phosphates
• RNA, Messenger
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers
• system N protein 1
• Ammonia
• Creatinine
• Glutaminase
• Pck1 protein, rat
• Phosphoenolpyruvate Carboxykinase (GTP)

Topics

• Acidosis (genetics)
• Amino Acid Transport Systems, Neutral (metabolism)
• Ammonia (metabolism)
• Animals
• Bicarbonates (chemistry)
• Creatinine (metabolism)
• Disease Models, Animal
• Gene Expression Regulation
• Glutaminase (metabolism)
• Heterozygote
• Hydrogen-Ion Concentration
• Intracellular Signaling Peptides and Proteins (metabolism)
• Kidney (metabolism, physiopathology)
• Phosphates (metabolism)
• Phosphoenolpyruvate Carboxykinase (GTP) (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Renal Insufficiency, Chronic (genetics, metabolism, urine)
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers (metabolism)