Regulation of renal glutamine metabolism in the rat

Parry, David (1977) Regulation of renal glutamine metabolism in the rat. Masters thesis, Memorial University of Newfoundland.

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Abstract

One means whereby the mammalian kidney excretes strong acid is by the formation of neutral ammonium salts in the urine. In response to a continuous acid challenge, the rate of ammonia excretion increases to meet the increased acid load. In the present study a strong acid load was administered to rats for 7 days, Ammonia excretion increased slowly reaching plateau levels after about three days. After the acid challenge was discontinued, the rats were placed back on tap water and allowed to recover. Ammonia excretion abruptly fell to normal within 24 hours. Phosphate dependent glutaminase (PDG) activity, the penetration of glutamine into mitochondria (the site of PDG) and phosphoenolpyruvate carboxykinase (PEPCK) activity have all been considered as rate-determining for the renal production of ammonia. For this reason the activities of PDG and PEPCK were measured in vitro during adaptation and recovery. Also glutamine metabolism (ammonia production and oxygen consumption) and the metabolism (oxygen consumption) of related substrates (glutamate, a-ketoglutarate and succinate) by isolated kidney cortex mitochondria were followed . In addition, glutamine metabolism (glutamine utilization, ammonia production, glutamate formation and glucose production) and the metabolism (glucose production) of related substrates (oxaloacetate, malate, lactate and pyruvate) by kidney cortex slices were measured during recovery. Mitochondrial capacity (PDG activity, oxygen consumption and ammonia production from glutamine) appears to correlate with the excretion of ammonia in the urine during adaptation. This correlation is consistent with ammonia production being regulated by a mitochondrial event. PEPCK attained maximum activity in vitro 24 hours before ammonia excretion reached its plateau. This suggests that the amount of PEPCK is not ratedetermining during adaptation. During recovery mitochondrial capacity remained at high plateau levels whereas the activity of PEPCK in vitro fell to normal values within 24 hours, The lack of a correlation between mitochondrial capacity and urine ammonia excretion suggests that renal ammonia production is not regulated solely by a mitochondrial event during recovery. No change in the mitochondrial metabolism of glutamate, a-ketoglutarate or succinate was observed during either adaptation or recovery. The remarkable correlation found during recovery between PEPCK activity in vitro, the metabolism of glutamine and related substrates by kidney cortex slices, and urinary ammonia excretion is consistent with PEPCK playing a regulatory role in ammonia production during this phase. Glutamine arteria-renal venous differences were also measured during adaptation and recovery and at all times paralleled the rate of ammonia excretion in the urine. Blood pH, [HCO)-₃, and pCO₂ were followed to help assess their possible regulatory significance. No simple correlation appears to exist between any of these parameters and urinary ammonia excretion. Rats recovering from 7 days of acid challenge were also starved. During this starved recovery PEPCK decreased slightly but remained elevated, yet ammonia excretion returned to normal. This dissociation is not consistent with this enzyme alone being regulatory for ammonia production. Rats were also returned to tap water after only 3 days of acid challenge. In comparison to recovery from 7 days of acid challenge urinary ammonia excretion persisted for an additional 24 hours. Since the acid~base status of the animal was shown to improve only after ammonia excretion had been fully adapted ~or some t~me~ then the persistence of elevated ammonia excretion supports the idea that the excretion of ammonia during recovery is related to restoration of acid-base balance.

Item Type: Thesis (Masters)
URI: http://research.library.mun.ca/id/eprint/12292
Item ID: 12292
Additional Information: Includes bibliographical references (pages 106-112).
Department(s): Science, Faculty of > Biochemistry
Date: March 1977
Date Type: Submission
Library of Congress Subject Heading: Glutamine metabolism; Kidneys; Nitrogen excretion

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