Glutamine Transport in Rat Kidney Mitochondria in Metabolic Acidosis

Adam, W. R.; Simpson, David P.

doi:10.1172/jci107738

Cited by 76 publications

(19 citation statements)

References 34 publications

(34 reference statements)

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“…Presently two theories of regulation have considerable merit. First, ammoniagenesis is controlled by an adaptive specific increase in the transport of glutamine into renal mitochondria in chronic acidosis (29,30). This implies substrate control of the intramitochondrial phosphate-dependent glutaminase.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of ammonia production and excretion in the rabbit by inorganic phosphate. Study of control mechanisms.

Yu¹,

Giammarco²,

Goldstein³

et al. 1976

J. Clin. Invest.

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A B S T R A C T The purpose of this study was to clarify the mechanism (s) responsible for regulation of ammonia production and excretion in the rabbit. The normally low ammonia excretion rate during acute metabolic acidosis was stimulated acutely and increased approximately ninefold after infusion of sodium phosphate, but remained low if sodium sulphate or Tris was substituted for phosphate. Ammonia production was increased significantly by phosphate in rabbit renal cortex slices and in isolated renal cortex mitochondria.In isolated mitochotidria, mersalyl, an inhibitor of both the phosphate/hydroxyl and phosphate/dicarboxylate mitochondrial carriers, inhibited the phosphateinduced stimulation, indicating that phosphate must enter the mitochondrion for stimulation. A malate/phosphate exchange seemed to be involved since N-ethylmaleimide, an inhibitor of the phosphate/hydroxyl exchange, did not inhibit phosphate-stimulated ammonia production, whereas there was inhibition by 2-n-butylmalonate, a competitive inhibitor of the dicarboxylate carrier. Phosphate itself was not essential since malonate stimulated ammoniagenesis in the absence of added phosphate. Similarly, citrate stimulated ammoniagenesis in isolated mitochondria in the absence of inorganic phosphate provided that it induced L-malate exit on the citrate transporter associated with inhibition of citrate oxidation by fluoroacetate. Similar results were also seen in mitochondria from rat renal cortex.Dr. Yu and Dr. Giammarco are postdoctoral Fellows, Medical Research Council of Canada.Received for putblication 11 December 1975 and in revised form 19 April 1976. A fall in mitochondrial a-ketoglutarate level resulted in an increase in ammonia production. This could be achieved directly with malonate or indirectly via L-malate exit. Simultaneous measurements of glutamate showed that the rate of ammonia production was reciprocally related to the glutamate content. We conclude that phosphate-induced stimulation of ammoniagenesis in the rabbit kidney is mediated by removal of glutamate, the feedback inhibitor of phosphate-dependent glutaminase. Glutamate removal is linked to phosphateinduced dicarboxylate exit across the mitochondrial membrane. INTRODUCTIONThe regulatory mechanisms involved in increased renal glutamine extraction, deamidation, and deamination during metabolic acidosis play a major role in acid-base homeostasis by permitting increased urine excretion of hydrogen ions in the form of ammonium. Urine ammonia excretion increases during metabolic acidosis in man, rat, and dog. However, despite many attempts to gain an understanding of this phenomenon, confusion still exists as to the role various mechanisms play (1-3).Previous studies have shown that ammonia excretion varies markedly from species to species, carnivores having a high rate of excretion (1-3) and herbivores a low rate of excretion (4). Several factors may be involved. Rats and dogs tend to have a neutral or acidic urine while rabbits, which are low ammonia excretors, have an alkali...

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Section: Discussionmentioning

confidence: 99%

Stimulation of ammonia production and excretion in the rabbit by inorganic phosphate. Study of control mechanisms.

Yu¹,

Giammarco²,

Goldstein³

et al. 1976

J. Clin. Invest.

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“…It is unlikely that intracellular accumulation of ammonia free-base affects the transport of glutamine directly at the peritubular border since intravenous infusion of ammonium chloride induces a rise in pNH3 and decreased glutamine extraction from the renal blood while the concentration of free glutamine in the renal cortical cells actually increases (18). On the other hand, ammonia could modify the transport of glutamine-across the mitochondrial membrane within the renal tubular cell since such a transport appears to be a rate-limiting factor in the utilization of glutamine and production of ammonia in chronic acidosis (22).…”

Section: Discussionmentioning

confidence: 99%

Renal Hemodynamics and Ammoniagenesis

Lemieux¹,

Vinay²,

Cartier³

1974

J. Clin. Invest.

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A B S T R A C T Renal production of ammonia by the left kidney was studied in 31 acidotic dogs (NH4Cl) after acute constriction of the renal artery. Renal ammoniagenesis fell in direct proportion with the reduction in glomerular filtration rate and renal plasma flow. The renal extraction of glutamine by the experimental kidney fell in direct proportion with the reduction in renal hemodynamics. Extracted glutamine remained greater than filtered glutamine indicating that both the luminal and antiluminal transport sites were operative. The relationship between renal extraction of glutamine and ammoniagenesis observed during control was maintained after renal artery constriction (1.7 Amol NH8 produced for each /Amol of glutamine extracted). Systemic venous or renal intra-arterial infusion of glutamine during arterial conlstriction increasedl renal production of ammonia to or above control values. These observations indicate that the mechanisms responsible for glutamine extraction and ammonia production were operating normally despite reduced rhemodynamics. When measured immediately after arterial clamping, the renal venous pNH3 was found to rise significantly decreasing progressively thereafter towards control values. The extracted fraction of total glutamine deJivered to the kidney (31%) did not clhange after acuite reduictioni of the glutaminie load. Thus, the antiluminal extraction site was incapable of lowerinig renal venious plasma glutamine concentration below 0.33 utM/ml. In a second series of experiments, the properties of the antiluminal site of transport for glutamine were studied after complete ocThis work was presented in part at the 5th International

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“…Other workers have demonstrated an in crease in ammonia production and glutamine uptake by mitochondria from acidotic ani mals and they have also found that the rapid uptake of glutamine is inhibited by sub stances which react directly with glutaminase [1].…”

Section: Discussionmentioning

confidence: 97%

“…Approximately 2.5 mg mitochondrial pro tein was incubated in 3 ml medium containing 130 mA/ KC1, 20 mA/ HEPES, 0.5 mA/ MgSC>4, 1.25 mA/ KH2P 0 4, 2 mg/ml bovine serum albumin [1], 2 mA/ glutamine with or without 4 mA/ sodium azide. In control experiments 4 mA/ NaCl was added.…”

Section: Mitochondriamentioning

confidence: 99%

See 1 more Smart Citation

Sodium-Dependent and Sodium-Independent Glutamine Transport in the Control of Ammoniagenesis in Rat Kidney

McFarlane‐Anderson¹,

Alleyne²

1978

Kidney Blood Press Res

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Our experiments show Na⁺-dependent and Na⁺-independent uptake of glutamine by renal cortical slices. In a Na⁺-containing buffer, sodium azide stimulates glutamine uptake and ammoniagenesis in slices from normal rats but has no effect on slices from acidotic rats. In Na⁺-free buffers azide does not alter ammoniagenesis or glutamine uptake by slices from normal rats but decrease both in slices from acidotic rats. Azide decreases ammoniagenesis in mitochondria from normal rats but increases it in mitochondria from acidotic rats. We conclude that azide stimulates Na⁺-dependent glutamine uptake and Na+-independent uptake may be stimulated by acidosis.

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Glutamine Transport in Rat Kidney Mitochondria in Metabolic Acidosis

Cited by 76 publications

References 34 publications

Stimulation of ammonia production and excretion in the rabbit by inorganic phosphate. Study of control mechanisms.

Stimulation of ammonia production and excretion in the rabbit by inorganic phosphate. Study of control mechanisms.

Renal Hemodynamics and Ammoniagenesis

Sodium-Dependent and Sodium-Independent Glutamine Transport in the Control of Ammoniagenesis in Rat Kidney

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