Proximal tubule glutamine synthetase expression is necessary for the normal response to dietary protein restriction.
Dietary protein restriction has multiple benefits in kidney disease. Because protein intake is a major determinant of endogenous acid production, it is important that net acid excretion changes in parallel during changes in dietary protein intake. Dietary protein restriction decreases endogenous acid production and decreases urinary ammonia excretion, a major component of net acid excretion. Glutamine synthetase (GS) catalyzes the reaction of [Formula: see text] and glutamate, which regenerates the essential amino acid glutamine and decreases net ammonia generation. Because renal proximal tubule GS expression increases during dietary protein restriction, this could contribute to the decreased ammonia excretion. The purpose of the current study was to determine the role of proximal tubule GS in the renal response to protein restriction. We generated mice with proximal tubule-specific GS deletion (PT-GS-KO) using Cre-loxP techniques. Cre-negative (Control) and PT-GS-KO mice in metabolic cages were provided 20% protein diet for 2 days and were then changed to low-protein (6%) diet for the next 7 days. Additional PT-GS-KO mice were maintained on 20% protein diet. Dietary protein restriction caused a rapid decrease in urinary ammonia excretion in both genotypes, but PT-GS-KO blunted this adaptive response significantly. This occurred despite no significant genotype-dependent differences in urinary pH or in serum electrolytes. There were no significant differences between Control and PT-GS-KO mice in expression of multiple other proteins involved in renal ammonia handling. We conclude that proximal tubule GS expression is necessary for the appropriate decrease in ammonia excretion during dietary protein restriction.
Division of Nephrology, Hypertension and Transplantation, University of Florida College of Medicine, Gainesville, Florida; and.
Hyun-Wook
HW
Lee
Division of Nephrology, Hypertension and Transplantation, University of Florida College of Medicine, Gainesville, Florida; and.
Gunars
G
Osis
Division of Nephrology, Hypertension and Transplantation, University of Florida College of Medicine, Gainesville, Florida; and.
Mary E
ME
Handlogten
Division of Nephrology, Hypertension and Transplantation, University of Florida College of Medicine, Gainesville, Florida; and.
Jill W
0000-0002-4096-4897
JW
Verlander
Division of Nephrology, Hypertension and Transplantation, University of Florida College of Medicine, Gainesville, Florida; and David.Weiner@medicine.ufl.edu.|Nephrology and Hypertension Section, North Florida/South Georgia Veterans Health System, Gainesville, Florida.
I David
0000-0002-0046-0600
ID
Weiner
D000222:Adaptation, Physiological; D000641:Ammonia / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000652:urine; D027682:Cation Transport Proteins / Q000378:metabolism; D018753:Diet, Protein-Restricted; D004044:Dietary Proteins / Q000378:metabolism*; D005838:Genotype; D005974:Glutamate-Ammonia Ligase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D065667:Renal Elimination; D013997:Time Factors; D014508:Urea / Q000652:urine
D015415:Biomarkers; D027682:Cation Transport Proteins; D004044:Dietary Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C486033:RhBG protein, mouse; C485880:Rhcg protein, mouse; D000641:Ammonia; D014508:Urea; D005974:Glutamate-Ammonia Ligase
acid-base; ammonia; dietary protein; proximal tubule