title: Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism.
abstract: Glutamine synthetase (GS) catalyzes the recycling of NH4 (+) with glutamate to form glutamine. GS is highly expressed in the renal proximal tubule (PT), suggesting ammonia recycling via GS could decrease net ammoniagenesis and thereby limit ammonia available for net acid excretion. The purpose of the present study was to determine the role of PT GS in ammonia metabolism under basal conditions and during metabolic acidosis. We generated mice with PT-specific GS deletion (PT-GS-KO) using Cre-loxP techniques. Under basal conditions, PT-GS-KO increased urinary ammonia excretion significantly. Increased ammonia excretion occurred despite decreased expression of key proteins involved in renal ammonia generation. After the induction of metabolic acidosis, the ability to increase ammonia excretion was impaired significantly by PT-GS-KO. The blunted increase in ammonia excretion occurred despite greater expression of multiple components of ammonia generation, including SN1 (Slc38a3), phosphate-dependent glutaminase, phosphoenolpyruvate carboxykinase, and Na(+)-coupled electrogenic bicarbonate cotransporter. We conclude that 1) GS-mediated ammonia recycling in the PT contributes to both basal and acidosis-stimulated ammonia metabolism and 2) adaptive changes in other proteins involved in ammonia metabolism occur in response to PT-GS-KO and cause an underestimation of the role of PT GS expression.
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Hyun-Wook
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Gunars
authors.initials: G
authors.lastname: Osis
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Mary E
authors.initials: ME
authors.lastname: Handlogten
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; and.
authors.forename: Farrukh A
authors.initials: FA
authors.lastname: Chaudhry
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Jill W
authors.initials: JW
authors.lastname: Verlander
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida; Nephrology and Hypertension Section, North Florida/South Georgia Veterans Health System, Gainesville, Florida David.Weiner@Medicine.ufl.edu.
authors.forename: I David
authors.identifier: 0000-0002-0046-0600
authors.initials: ID
authors.lastname: Weiner
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000235:genetics* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001639:Bicarbonates; D027682:Cation Transport Proteins; D000641:Ammonia; D005974:Glutamate-Ammonia Ligase
keywords: acid-base; ammonia; glutamine synthetase; proximal tubule