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Proximal Tubule Glutamine Synthetase is Critical for the Response to Low Protein Diet
Author(s) -
Weiner I. David,
Lee HyunWook,
Osis Gunars,
Handlogten Mary E.,
Chen Chao,
Verlander Jill W.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.857.23
Subject(s) - excretion , glutamine synthetase , glutamine , medicine , endocrinology , metabolism , ammonia , chemistry , net acid excretion , kidney , endogeny , biology , biochemistry , amino acid
The mechanisms through which the kidneys increase ammonia generation in response to increased endogenous acid loads have been extensively studied; the mechanisms underlying decreased ammonia metabolism are less well understood. Glutamine synthetase is expressed in the kidney, and mediates reaction of NH 4 + with glutamate, generating glutamine and decreasing net ammonia generation. Our previous studies show that dietary protein restriction, which decreases endogenous acid production, increases proximal tubule glutamine synthetase expression. The purpose of the current studies was to determine the functional importance of glutamine synthetase in the response to dietary protein restriction. We used mice with proximal tubule‐specific glutamine synthetase deletion (PT‐GS‐KO), using floxed GS alleles and Cre‐recombinase under control of the PEPCK promoter. Control (C) mice was floxed, Cre‐negative littermates. Mice were studied in metabolic cages, and daily 24‐hour urine samples collected. Changing from normal, 20%, protein to low, 6%, protein diets for one week resulted in a rapid decrease in urinary ammonia excretion that was maximal at day 2 in C mice. In PT‐GS‐KO mice, the ability to decrease ammonia excretion was impaired significantly on day 2–7 as compared to C mice. This impaired ability to alter urinary ammonia excretion occurred despite no significant difference in urine pH on any day between C and PT‐GS‐KO mice. The difference in ammonia excretion was unique to this component of net acid excretion; titratable acid excretion did not differ significantly between C and PT‐GS‐KO mice. Other components of renal ammonia metabolism, specifically PDG, PEPCK, NHE3, NKCC2, Rhbg and Rhcg, were not detectably different between C and PT‐GS‐KO mice. We conclude that glutamine synthetase, whose expression increases in response to dietary protein restriction, is necessary for adaptive changes in renal ammonia excretion, thereby enabling maintenance of acid‐base homeostasis and nitrogen metabolism. Support or Funding Information The studies were supported by funds from the NIH (R01‐DK045788 and R01‐DK107798) and from the Department of Veterans Affairs (1I01BX000818).