Adaptation of renal tricarboxylic acid cycle metabolism to various acid-base states: study with [3-13C,5-15N]glutamine.
We studied mechanism(s) by which adaptations of renal TCA cycle metabolism abet ammoniagenesis from glutamine in altered acid-base states. Renal tubules from control, acidotic, or alkalotic rats were incubated at pH 7.4 with 1 mM [3-13C,5-15N]glutamine or 2 mM [3-13C]pyruvate. In acidosis there was a significantly higher flux through glutaminase and through glutamate, 2-oxoglutarate, succinate and malate dehydrogenases as well as markedly enhanced 13C-glucose formation. Alkalosis was associated with little change in 13C flux from glutamine to TCA cycle intermediates compared with control but production of 15NH3 and 13C glucose was significantly diminished. The current studies indicate that renal ammoniagenesis might be regulated at the sites of citrate synthetase (CS) and/or alpha-ketoglutarate dehydrogenase (KGDH). Thus, in chronic metabolic acidosis decreased flux through CS and increased flux through KGDH resulted in enhanced flux through glutamate dehydrogenase and glutaminase pathway. The opposite occurred in alkalosis. The data suggest that in various acid-base states the rate of renal gluconeogenesis is linearly correlated with malate efflux from the mitochondria. In renal tissue, inhibition occurs at one site of the TCA cycle there is an augmentation of fluxes through pathways beyond that site in order to maintain the respiratory process and the redox state in the mitochondria.
Nissim
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Division of Biochemical Development and Molecular Diseases, Children's Hospital of Philadelphia, Pa.
Nissim
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Yudkoff
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D000137:Acid-Base Imbalance / Q000378:metabolism*; D000138:Acidosis / Q000378:metabolism; D000222:Adaptation, Physiological; D000471:Alkalosis / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000378:metabolism; D002952:Citric Acid Cycle; D005947:Glucose / Q000378:metabolism; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005972:Glutaminase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D005973:Glutamine; D001224:Aspartic Acid; D000641:Ammonia; D007655:Ketoglutarate Dehydrogenase Complex; D005969:Glutamate Dehydrogenase; D002950:Citrate (si)-Synthase; D005972:Glutaminase; D005947:Glucose