Complexity of glutamine metabolism in kidney tubules from fed and fasted rats

Vercoutère, Barbara; Durozard, Daniel; Baverel, Gabriel; Martin, G.

doi:10.1042/bj20031088

Cited by 24 publications

(20 citation statements)

References 58 publications

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“…Both FOXO1 and GS are upregulated in conditions associated with muscle atrophy (20,21), such as fasting, diabetes, and advanced cancer (20,21). Glutamine synthesized by GS may serve as a substrate for gluconeogenesis during fasting and diabetes (29,32). In advanced cancer, glutamine serves as an energy source for tumor growth (7).…”

Section: Discussionmentioning

confidence: 99%

FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3′-UTR: possible contribution to ammonia detoxification

Kamei

Hattori

Hatazawa

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Skeletal muscle is a reservoir of energy in the form of protein, which is degraded under catabolic conditions, resulting in the formation of amino acids and ammonia as a byproduct. The expression of FOXO1, a forkhead-type transcription factor, increases during starvation and exercise. In agreement, transgenic FOXO1-Tg mice that overexpress FOXO1 in skeletal muscle exhibit muscle atrophy. The aim of this study was to examine the role of FOXO1 in amino acid metabolism. The mRNA and protein expressions of glutamine synthetase (GS) were increased in skeletal muscle of FOXO1-Tg mice. Fasting induced FOXO1 and GS expression in wild-type mice but hardly increased GS expression in muscle-specific FOXO1 knockout (FOXO1-KO) mice. Activation of FOXO1 also increased GS mRNA and protein expression in C2C12 myoblasts. Using a transient transfection reporter assay, we observed that FOXO1 activated the GS reporter construct. Mutation of a putative FOXO1-binding consensus sequence in the downstream genomic region of GS decreased basal and FOXO1-dependent reporter activity significantly. A chromatin immunoprecipitation assay showed that FOXO1 was recruited to the 3′ region of GS in C2C12 myoblasts. These results suggest that FOXO1 directly upregulates GS expression. GS is considered to mediate ammonia clearance in skeletal muscle. In agreement, an intravenous ammonia challenge increased blood ammonia concentrations to a twofold higher level in FOXO1-KO than in wild-type mice, demonstrating that the capacity for ammonia disposal correlated inversely with the expression of GS in muscle. These data indicate that FOXO1 plays a role in amino acid metabolism during protein degradation in skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3′-UTR: possible contribution to ammonia detoxification

Kamei

Hattori

Hatazawa

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…The GS increase during development until adulthood could be explained by the requirement of more glutamine, an important renal glucose precursor and energy provider (Vercoutère et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of aging influence on renal toxicity caused by segment‐specific nephrotoxicants of the proximal tubule in rat†

Zanetti

Chiusolo

Defazio

et al. 2009

J of Applied Toxicology

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Little is known concerning the sensitivity of aged rats to xenobiotics inducing kidney damage. To increase this knowledge, the age-dependent response of the kidney to hexachloro-1 : 3-butadiene (HCBD) or potassium dichromate (chromate) was investigated. Rats were treated at different ages with a single dose of segment-specific nephrotoxicants of the proximal tubule, chosen on the basis of their specificity for S(3) and for S(1)-S(2) segments, respectively. The toxicological impact of these xenobiotics has been evaluated through biochemical and genomic markers, and histopathological investigation of kidney samples. HCBD treatment induced tubular necrosis of the S(3) segment of the proximal tubule associated with changes of toxicological markers unrelated to the age. In contrast, chromate treatment induced an increased kidney damage related to the rat age. In fact, histopathological investigation revealed that at 1 month of age tubular vacuolar degeneration was seen affecting S(1)-S(2) segments of the proximal tubule, whereas at 3 months of age tubular necrosis occurred in the same segments associated with tubular dilation of the distal portions. Consistently, biochemical analysis confirmed a direct correlation among genomic and biochemical marker variability and animal age. Altogether, the results show that during aging there is an increased sensitivity of kidney to chromate but not to HCBD-induced damage and evidence differential age-related selectivity of rats for nephrotoxic compounds. Significance for human risk assessment is discussed.

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“…Transaminases were not determined in our experiment; however, during energy needs, as indicated by Vercoutere et al [34], other amino acids keep cellular glutamate levels constant while the energy providers such as glutamine are shifted to the metabolic pathways to provide glucose and CO 2 or other products in the proximal tubule cells.…”

Section: Discussionmentioning

confidence: 99%

“…L -Glutamine is involved in a variety of metabolic pathways and plays a key role in many physiological processes [34]. In proximal tubule cells, L -glutamine is used both in the transamidation and the deamidation pathways [16, 32].…”

Section: Discussionmentioning

confidence: 99%

Effect of Nitric Oxide on Ammoniagenesis in Rats

Cırrık

Öner

2006

Nephron Physiol

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Aim: This in vitro study using rat cortical slices, isolated proximal tubules and mitochondria was conducted to investigate the effect of exogenous and endogenous nitric oxide on ammoniagenesis. Methods and Results: The cortical slices were incubated with phosphate-buffered saline containing 1 mML-glutamine at 37°C andglutamine-stimulated ammoniagenesis which was further elevated with 10^–7M ANGII showed a time-dependent decrease during 2 h. 10^–4M L-NAME or 10^–5ML-canavanin caused a similar ammonia elevation to that of ANGII, whereas the addition of 10^–5M SNAP attenuated the ammonia-increasing effects of ANGII and L-NAME. Basal or exogenous NO without significantly affecting glutamine uptake of the slices seemed to convert the glutamine deamidation pathway to transamination, since L-NAME increased the ammonia to glutamine ratio from 0.87 ± 0.08 mol/mol to 1.03 ± 0.04 (p < 0.01). L-NAME increased both ammoniagenesis and mitochondrial oxygen consumption but SNAP depressed them. Endogenous NO reduced ammoniagenesis without changing the mitochondrial permeability transition pore (PTP), whereas exogenous NO-induced attenuation in ammoniagenesis was associated with elevated PTP in a CsA-sensitive manner. Conclusion: These results demonstrated that in rat kidney, basal NO depresses mitochondrial oxygen consumption and attenuates ammoniagenesis without affecting PTP; however, exogenous NO inhibits ammonia production by disturbing PTP in isolated mitochondria.

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Complexity of glutamine metabolism in kidney tubules from fed and fasted rats

Cited by 24 publications

References 58 publications

FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3′-UTR: possible contribution to ammonia detoxification

FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3′-UTR: possible contribution to ammonia detoxification

Evaluation of aging influence on renal toxicity caused by segment‐specific nephrotoxicants of the proximal tubule in rat†

Effect of Nitric Oxide on Ammoniagenesis in Rats

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