Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

Weiner, I. David; Mitch, William E.; Sands, Jeff M.

doi:10.2215/cjn.10311013

Cited by 366 publications

(306 citation statements)

References 101 publications

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“…The relation between glutamine-bound ammonia disposal as urea and glutamine production was investigated with [5][6][7][8][9][10][11][12][13][14][15] N-L-glutamine ("glutamine11") and 18 O-, 13 C-urea ("urea13"). Steady-state blood concentrations of glutamine11 were attained after 30 minutes and those of urea13 after 90 minutes.…”

Section: Whole-body Glutamine and Urea Synthesis In Gs-deficient Micementioning

confidence: 99%

“…GS deficiency causes only moderate hyperammonemia, but affected humans and mice suffer from encephalopathy and die neonatally. (2,3) GS is predominantly expressed in the nervous system, kidney, and liver, that is, in established glutamine-consuming organs, (4)(5)(6) whereas skeletal muscle, with a much lower expression but large mass, is considered the main net producer of glutamine. (7) The nervous system synthesizes glutamine to scavenge /Gs fl/fl mice; GS-KO/0.5, Gs fl/LacZ mice; K 0.5 , substrate concentration at which process proceeds at 50% of maximum velocity; KO, knockout; MSO, methionine sulfoximine.…”

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confidence: 99%

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Pivotal role of glutamine synthetase in ammonia detoxification

et al. 2017

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Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole-body muscle-to-fat ratio with increased myostatin expression in muscle. Using GS-knockout/liver and control mice and stepwise increments of enterally infused ammonia, we show that 35% of this ammonia is detoxified by hepatic GS and 35% by urea-cycle enzymes, while 30% is not cleared by the liver, independent of portal ammonia concentrations £ 2 mmol/L. Using both genetic (GSknockout/liver and GS-knockout/muscle) and pharmacological (methionine sulfoximine and dexamethasone) approaches to modulate GS activity, we further show that detoxification of stepwise increments of intravenously (jugular vein) infused ammonia is almost totally dependent on GS activity. Maximal ammonia-detoxifying capacity through either the enteral or the intravenous route is 160 lmol/hour in control mice. Using stable isotopes, we show that disposal of glutaminebound ammonia to urea (through mitochondrial glutaminase and carbamoylphosphate synthetase) depends on the rate of glutamine synthesis and increases from 7% in methionine sulfoximine-treated mice to 500% in dexamethasone-treated mice (control mice, 100%), without difference in total urea synthesis. Conclusions: Hepatic GS contributes to both enteral and systemic ammonia detoxification. Glutamine synthesis in the periphery (including that in pericentral hepatocytes) and glutamine catabolism in (periportal) hepatocytes represents the high-affinity ammonia-detoxifying system of the body. The dependence of glutamine-bound ammonia disposal to urea on the rate of glutamine synthesis suggests that enhancing peripheral glutamine synthesis is a promising strategy to treat hyperammonemia. Because total urea synthesis does not depend on glutamine synthesis, we hypothesize that glutamate dehydrogenase complements mitochondrial ammonia production. (HEPATOLOGY 2017;65:281-293). G lutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. (Note: NH 3 is protonated for 98% to NH 4 1 at physiological pH. We use the term "ammonia" to refer to the sum of NH 3 and NH 4 1 unless specified as either "NH 3 " or "NH 41 .") Glutamine serves, with alanine, as a major nontoxic interorgan ammonia shuttle in the body (1) and as an aminomoiety donor for the synthesis of nucleotides, amino acids, amino-sugars, and oxidized nicotinamide adenine dinucleotide. Its intracellular turnover rate exceeds that of all other amino acids. GS deficiency causes only moderate hyperammonemia, but affected humans and mice suffer from encephalopathy and die neonatally. (2,3) GS is predominantly expressed in the nervous system, kidney, and liver, that is, in established glutamine-consuming organs, (4)(5)(6) whereas skeletal muscle, with a much lower expression but large mass, is considered the main net ...

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Section: Whole-body Glutamine and Urea Synthesis In Gs-deficient Micementioning

confidence: 99%

mentioning

confidence: 99%

Pivotal role of glutamine synthetase in ammonia detoxification

et al. 2017

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“…Urea recycling and its reabsorption in the inner medullary collecting duct (IMCD) by UTA1 and UTA3 transporters play an important role in the fine tuning of renal water reabsorption (41,42). However, urea is an ineffective solute; when its rate of excretion increases (e.g., urea tablets, high-protein diet, post-ATN diuresis, or postobstructive diuresis), urea cannot be absorbed rapidly enough to equilibrate between the tubular lumen and the intracellular space of collecting duct (CD) cells.…”

Section: Promoting Renal Water Excretionmentioning

confidence: 99%

Mild Chronic Hyponatremia in the Ambulatory Setting

Rondon‐Berrios

Berl

2015

Clinical Journal of the American Society of Nephrology

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Mild chronic hyponatremia, as defined by a persistent (>72 hours) plasma sodium concentration between 125 and 135 mEq/L without apparent symptoms, is common in ambulatory patients and generally perceived as being inconsequential. The association between increased mortality and hyponatremia in hospitalized patients in various settings and etiologies is widely recognized. This review analyzes the significance of mild chronic hyponatremia in ambulatory subjects and its effects on mortality and morbidity. It addresses whether this disorder should even be treated and if so, which patients are likely to benefit from treatment. The available approaches to correct hyponatremia in such patients in the context of recently published panel-generated recommendations and guidelines are described.

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“…The connecting segment and collecting duct rely mostly on their intercalated cells to reabsorb the normally smaller amount of residual bicarbonate. In addition, intercalated cells participate in the excretion of ammonia/ammonium, a topic reviewed in a separate article in this series (9).…”

Section: Introductionmentioning

confidence: 99%

Collecting Duct Intercalated Cell Function and Regulation

Roy¹,

Al‐bataineh²,

Pastor-Soler

2015

Clinical Journal of the American Society of Nephrology

211

213

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Intercalated cells are kidney tubule epithelial cells with important roles in the regulation of acid-base homeostasis. However, in recent years the understanding of the function of the intercalated cell has become greatly enhanced and has shaped a new model for how the distal segments of the kidney tubule integrate salt and water reabsorption, potassium homeostasis, and acid-base status. These cells appear in the late distal convoluted tubule or in the connecting segment, depending on the species. They are most abundant in the collecting duct, where they can be detected all the way from the cortex to the initial part of the inner medulla. Intercalated cells are interspersed among the more numerous segment-specific principal cells. There are three types of intercalated cells, each having distinct structures and expressing different ensembles of transport proteins that translate into very different functions in the processing of the urine. This review includes recent findings on how intercalated cells regulate their intracellular milieu and contribute to acid-base regulation and sodium, chloride, and potassium homeostasis, thus highlighting their potential role as targets for the treatment of hypertension. Their novel regulation by paracrine signals in the collecting duct is also discussed. Finally, this article addresses their role as part of the innate immune system of the kidney tubule.

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Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

Cited by 366 publications

References 101 publications

Pivotal role of glutamine synthetase in ammonia detoxification

Pivotal role of glutamine synthetase in ammonia detoxification

Mild Chronic Hyponatremia in the Ambulatory Setting

Collecting Duct Intercalated Cell Function and Regulation

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