Metabolic effects of valproate on dog renal cortical tubules

1989 ◽  
Vol 67 (2) ◽  
pp. 88-97 ◽  
Author(s):  
André Gougoux ◽  
Patrick Vinay
Keyword(s):  
Proximal Tubules ◽  
Glutamine Metabolism ◽  
Metabolic Effects ◽  
Lactate Metabolism ◽  
Lactate And Pyruvate ◽  
Lactate Utilization ◽  
Sites Of Action ◽  
Glutamine Uptake ◽  
Stimulation Of

The effect of valproate (0.01–10 mM), an antiepileptic drug inducing hyperammonemia in humans, was studied in vitro on a suspension of renal cortical tubules (> 85% proximal tubules) obtained from six normal dogs. When these tubules were incubated with 1 mM glutamine, the addition of valproate accelerated glutamine uptake, ammoniagenesis, and the production of alanine, lactate, and pyruvate. With 5 mM glutamine, a rise in glutamate accumulation, a much greater synthesis of alanine, an important aspartate production, and a striking accumulation of lactate and pyruvate were observed. With 1 or 5 mM lactate, lactate utilization and gluconeogenesis were markedly reduced with increasing concentrations of valproate. Oxygen consumption was reduced by only 15–20% by 10 mM valproate. The accelerated glutamine utilization resulting from valproate could not be prevented by aminooxyacetate, an inhibitor of transamination. Valproate also reduced various enzymatic activities, a finding that could not explain its metabolic effects. Four sites of action may explain these various metabolic changes: (i) a stimulation of mitochondrial glutamine transport, (ii) an increase in the flux of glutamate to malate, and (iii) a reduction in the net oxidation of pyruvate and (iv) in the flux through pyruvate carboxylase.Key words: hyperammonemia, glutamine metabolism, ammoniagenesis, pyruvate, lactate metabolism.

Localization of central sites of action of angiotensin II on ADH release in vitro

1978 ◽  
Vol 234 (2) ◽  
pp. F135-F140
Author(s):  
C. M. Gregg ◽  
R. L. Malvin
Keyword(s):  
Angiotensin Ii ◽  
Direct Action ◽  
Central Effect ◽  
The Central Nervous System ◽  
Sites Of Action ◽  
Isolated Rat ◽  
Supraoptic Nuclei ◽  
Stimulation Of

It is now thought that angiotensin II can stimulate antidiuretic hormone (ADH) release in vivo by a direct action in the central nervous system but it is not known whether the locus of stimulation is the hypothalamus or the neurohypophysis or both. Isolated rat neural lobes incubated for 10 min in buffer containing angiotensin II (200 ng/ml or 2 microgram/ml) did not increase ADH release compared to control values, but addition of KCl (60 mM) to the bath markedly stimulated ADH release. However, intact hypothalamoneurohypophysial systems (containing the supraoptic nuclei) incubated with angiotensin II (200 ng/ml or 2 microgram/ml) did show a pronounced stimulation of ADH release. The data support the hypothesis that angiotensin II, at least in vitro, has a central effect on ADH release which is at the level of the hypothalamus.

scholarly journals Proteasome inhibition disrupts the metabolism of fumarate hydratase- deficient tumors by downregulating p62 and c-Myc

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Carole Sourbier ◽  
Christopher J. Ricketts ◽  
Pei-Jyun Liao ◽  
Shingo Matsumoto ◽  
Darmood Wei ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Fumarate Hydratase ◽  
Proteasome Inhibition ◽  
Glutamine Metabolism ◽  
Metabolic Effects ◽  
Cycle Enzyme

AbstractHereditary leiomyomatosis and renal cell carcinoma (HLRCC) is characterized by germline mutations of the FH gene that encodes for the TCA cycle enzyme, fumarate hydratase. HLRCC patients are at risk for the development of an aggressive form of type 2 papillary renal cell carcinoma. By studying the mechanism of action of marizomib, a proteasome inhibitor able to cross the blood-brain barrier, we found that it modulates the metabolism of HLRCC cells. Marizomib decreased glycolysis in vitro and in vivo by downregulating p62 and c-Myc. C-Myc downregulation decreased the expression of lactate dehydrogenase A, the enzyme catalyzing the conversion of pyruvate to lactate. In addition, proteasomal inhibition lowered the expression of the glutaminases GLS and GLS2, which support glutamine metabolism and the maintenance of the redox balance. Thus, in HLRCC cells, proteasome inhibition disrupts glucose and glutamine metabolism, restricting nutrients and lowering the cells’ anti-oxidant response capacity. Although the cytotoxicity induced by proteasome inhibitors is complex, the understanding of their metabolic effects in HLRCC may lead to the development of effective therapeutic strategies or to the development of markers of efficacy.

Alanine protects rabbit proximal tubules against anoxic injury in vitro

1990 ◽  
Vol 258 (4) ◽  
pp. F1075-F1083 ◽  
Author(s):  
R. Garza-Quintero ◽  
J. Ortega-Lopez ◽  
J. H. Stein ◽  
M. A. Venkatachalam
Keyword(s):  
Amino Acid ◽  
Glucose Metabolism ◽  
Atp Synthesis ◽  
Proximal Tubules ◽  
Severely Injured ◽  
Anoxic Injury ◽  
Anaerobic Fermentations ◽  
Related Amino Acid ◽  
Stimulation Of

Rabbit proximal tubules were incubated aerobically or subjected to anoxia for 30 min followed by 60 min of reoxygenation. The medium contained (in mM) 5 glucose, 10 butyrate, 4 lactate or alpha-ketoglutarate (alpha-KG), and 1 alanine. Anoxic tubules in this medium were severely injured and recovered poorly. If the incubation medium was supplemented with additional alanine (up to 2.5 or 5 mM), then anoxic injury was prevented almost completely. Tubules in high-alanine medium showed modest elevations of ATP during anoxia. Comparable elevations of ATP were induced in anoxic tubules incubated with 4 mM alpha-KG and 5 mM aspartate without alanine. These substrates are metabolized anaerobically in the mitochondria to yield ATP. Surprisingly, anoxic tubules with alpha-KG and aspartate showed severe injury despite elevated ATP. If 5 mM alanine was also present, then additional increments of ATP did not occur, but injury was prevented. Examination of glucose metabolism failed to provide evidence for stimulation of anaerobic fermentations by alanine. These results suggest that alanine-induced cytoprotection during anoxia occurs by mechanisms not related to ATP synthesis, and that elevated ATP in alanine-supplemented tubules may be a result and not the cause of protection. Cytoprotection by alanine was shown to last for less than or equal to 90 min of anoxia. Glycine, a structurally related amino acid, also protects anoxic proximal tubules (J. Clin. Invest. 80: 1446, 1987). The mechanisms that underlie the cytoprotective effects of alanine and glycine remain to be determined.

scholarly journals Role of Protein Kinase G in Growth and Glutamine Metabolism of Mycobacterium bovis BCG

2005 ◽  
Vol 187 (16) ◽  
pp. 5852-5856 ◽  
Author(s):  
Liem Nguyen ◽  
Anne Walburger ◽  
Edith Houben ◽  
Anil Koul ◽  
Stefan Muller ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mycobacterium Bovis ◽  
Glutamine Metabolism ◽  
Protein Kinase G ◽  
In Vitro Growth ◽  
Wild Type ◽  
Putative Operon ◽  
Glutamine Uptake

ABSTRACT The survival of pathogenic mycobacteria in macrophages requires the eukaryotic enzyme-like serine/threonine protein kinase G. This kinase with unknown specificity is secreted into the cytosol of infected macrophages and inhibits phagosome-lysosome fusion. The pknG gene is the terminal gene in a putative operon containing glnH, encoding a protein potentially involved in glutamine uptake. Here, we report that the deletion of pknG did not affect either glutamine uptake or intracellular glutamine concentrations. In vitro growth of Mycobacterium bovis BCG lacking pknG was identical to that of the wild type. We conclude that in M. bovis BCG, glutamine metabolism is not regulated by protein kinase G.

Gluconeogenesis from glutamine and lactate in the isolated humanrenal proximal tubule: longitudinal heterogeneity and lack of response to adrenaline

2001 ◽  
Vol 360 (2) ◽  
pp. 371-377 ◽  
Author(s):  
Agnès CONJARD ◽  
Mireille MARTIN ◽  
Jérôme GUITTON ◽  
Gabriel BAVEREL ◽  
Bernard FERRIER
Keyword(s):  
Proximal Tubule ◽  
Human Kidney ◽  
Glucose Production ◽  
Proximal Tubules ◽  
Renal Gluconeogenesis ◽  
Adrenaline Infusion ◽  
Gluconeogenic Substrates ◽  
Stimulation Of

Recent studies in vivo have suggested that, in humans in the postabsorptive state, the kidneys contribute a significant fraction of systemic gluconeogenesis, and that the stimulation of renal gluconeogenesis may fully explain the increase in systemic gluconeogenesis during adrenaline infusion. Given the potential importance of human renal gluconeogenesis in various physiological and pathophysiological situations, we have conducted a study in vitro to further characterize this metabolic process and its regulation. For this, successive segments (S1, S2 and S3) of human proximal tubules were dissected and incubated with physiological concentrations of glutamine or lactate, two potential gluconeogenic substrates that are taken up by the human kidney in vivo, and glucose production was measured. The effects of adrenaline, noradrenaline and cAMP, a well established stimulator of gluconeogenesis in animal kidney tubules, were also studied in suspensions of human renal proximal tubules. The results indicate that the three successive segments have about the same capacity to synthesize glucose from glutamine; by contrast, the S2 and S3 segments synthesize more glucose from lactate than the S1 segment. In the S2 and S3 segments, lactate appears to be a better gluconeogenic precursor than glutamine. The addition of cAMP, but not of adrenaline or noradrenaline, led to the stimulation of gluconeogenesis from lactate and glutamine by human proximal tubules. These results indicate that, in the human kidney in vivo, lactate might be the main gluconeogenic precursor, and that the stimulation of renal gluconeogenesis observed in vivo upon adrenaline infusion may result from an indirect action on the renal proximal tubule.

Organic mercurial diuresis: Inhibition of glutamine utilization in the acidotic rat

1979 ◽  
Vol 57 (3) ◽  
pp. 227-234
Author(s):  
Louise Passerini ◽  
T. C. Welbourne
Keyword(s):  
Glucose Production ◽  
Dry Weight ◽  
Glutamine Metabolism ◽  
Sodium Reabsorption ◽  
Active Sodium ◽  
Reduced Rate ◽  
Glutamine Uptake ◽  
Organic Mercurials ◽  
Isolated Kidneys

Organic mercurials inhibit mitochondrial glutamine metabolism in vitro while metabolic acidosis, a condition in which the predominant renal fuel is glutamine, potentiates mercurial diuresis. The following studies were undertaken to determine whether potentiation of diuresis reflects mercurial inhibition of glutamine utilization.(1) All three mercurials employed (mersalyl, chlormerodrin, and p-chloromercuribenzoate) are diuretics in the rat and this effect was potentiated by NH4Cl.(2) Despite reabsorbing less sodium, mercurial-treated rats had lower kidney ATP content (4.35 ± 0.26 and 3.85 ± 0.43 μmol/g dry weight (mercurial plus NH4Cl)) than did controls (4.95 ± 0.31 and 4.87 ± 0.39 μmol/g dry weight (NH4Cl)).(3) Isolated kidneys from NH4Cl and NH4Cl plus mercurial treated rats were perfused with 1 mML-[U-14C]glutamine to determine rates of extraction and oxidation. Mercurial-treated acidotic rat kidneys had a reduced rate of glutamine uptake (40.8 ± 7.4 vs. 64.8 ± 5.8 μmol/h. per kidney), a diminished rate of glutamine conversion to CO2 (14.8 ± 3.6 vs. 26.4 ± 5.2 μmol/h per kidney), and a reduction in glucose production (16 ± 5 vs. 27 ± 4 μmol/h per kidney). These results are consistent with an effect of organic mercurials upon glutamine utilization, limiting ATP availability, and thereby reducing tubular active sodium reabsorption.

scholarly journals Effect of phenylephrine on glutamate and glutamine metabolism in isolated perfused rat liver

1984 ◽  
Vol 221 (3) ◽  
pp. 651-658 ◽  
Author(s):  
D Häussinger ◽  
H Sies
Keyword(s):  
Glutamate Dehydrogenase ◽  
Rat Liver ◽  
Glutamine Metabolism ◽  
Isolated Perfused Rat Liver ◽  
Perfused Rat Liver ◽  
Alpha Adrenergic Receptors ◽  
14Co2 Production ◽  
Oxoglutarate Dehydrogenase ◽  
Glutamine Uptake ◽  
Stimulation Of

Addition of phenylephrine to isolated perfused rat liver is followed by an increased 14CO2 production from [1-14C]glutamate, [1-14C]glutamine, [U-14C]proline and [3-14C]pyruvate, but by a decreased 14CO2 production from [1-14C]pyruvate. Simultaneously, there is a considerable decrease in tissue content of 2-oxoglutarate, glutamate and citrate. Stimulation of 14CO2 production from [1-14C]glutamate is also observed in the presence of amino-oxyacetate, suggesting a stimulation of glutamate dehydrogenase and 2-oxoglutarate dehydrogenase fluxes by phenylephrine. Inhibition of pyruvate dehydrogenase flux by phenylephrine is due to an increased 2-oxoglutarate dehydroxygenase flux. Phenylephrine stimulates glutaminase flux and inhibits glutamine synthetase flux to a similar extent, resulting in an increased hepatic glutamine uptake. Whereas the effects of NH4+ ions and phenylephrine on glutaminase flux were additive, activation of glutaminase by glucagon was considerably diminished in the presence of phenylephrine. The reported effects are largely overcome by prazosin, indicating the involvement of alpha-adrenergic receptors in the action of phenylephrine. It is concluded that stimulation of gluconeogenesis from various amino acids by phenylephrine is due to an increased flux through glutamate dehydrogenase and the citric acid cycle.

scholarly journals Regulation by insulin of glucose metabolism in mammary gland of anaesthetized lactating rats. Stimulation of phosphofructokinase-1 by fructose 2,6-bisphosphate and activation of acetyl-CoA carboxylase

1988 ◽  
Vol 254 (1) ◽  
pp. 11-14 ◽  
Author(s):  
A F Burnol ◽  
S Ebner ◽  
P Ferré ◽  
J Girard
Keyword(s):  
Mammary Gland ◽  
Glucose Metabolism ◽  
Fold Increase ◽  
Maximal Activity ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Euglycaemic Hyperinsulinaemic Clamp ◽  
Sites Of Action ◽  
Stimulation Of

The effect of insulin on glucose metabolism in mammary gland was studied by the euglycaemic/hyperinsulinaemic-clamp technique. Measurement of metabolite concentrations and enzyme activities in the mammary gland suggests two sites of action of insulin: phosphofructokinase-1 and acetyl-coA carboxylase. The increase in phosphofructokinase-1 activity could be linked to the 2-fold increase in fructose 2,6-bisphosphate concentration, since no change in maximal activity and in sensitivity of the enzyme toward fructose 6-phosphate was detected in vitro.

scholarly journals ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma

2019 ◽  
Vol 122 (1) ◽  
pp. 82-93 ◽  
Author(s):  
Ze Zhang ◽  
Ruoyan Liu ◽  
Yanjie Shuai ◽  
Yuting Huang ◽  
Rui Jin ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Animal Studies ◽  
Neck Squamous Cell Carcinoma ◽  
Glutamine Metabolism ◽  
Glutamine Uptake

Abstract Background Glutamine is an abundant and versatile nutrient in cancer cells. Head and neck squamous cell carcinoma (HNSCC) was reported to be dependent on mainly glucose, not glutamine, for producing the energy required for survival and proliferation. Methods The roles of ASCT2 (SLC1A5) and associated glutamine metabolism were determined by the MTT, colony formation, glutamine uptake, intracellular glutathione, ROS detection, immunofluorescence, immunohistochemistry, and apoptosis enzyme-linked immunosorbent assays as well as animal studies. Results We found that glutamine is also critical for HNSCC. In this study, ASCT2, an amino acid transporter responsible for glutamine transport, in addition to LAT1 and GLS, is overexpressed in HNSCC and associated with poor survival. Using both in vivo and in vitro models, we found that knocking down ASCT2 by shRNAs or miR-137 or the combination of silencing ASCT2 and pharmacologically inhibiting SNAT2 via a small-molecule antagonist called V-9302 significantly suppressed intracellular glutamine levels and downstream glutamine metabolism, including glutathione production; these effects attenuated growth and proliferation, increased apoptosis and autophagy, and increased oxidative stress and mTORC1 pathway suppression in HNSCC. Additionally, silencing ASCT2 improved the response to cetuximab in HNSCC. Conclusions In summary, ASCT2-dependent glutamine uptake and subsequent glutamine metabolism are essential for HNSCC tumorigenesis, and the combination of glutamine uptake inhibitors and cetuximab presents a promising strategy for improving the outcomes of HNSCC patients.

L-glutamine with D-glucose stimulates oxidative metabolism and NaCl absorption in piglet jejunum

1992 ◽  
Vol 263 (6) ◽  
pp. G960-G966 ◽  
Author(s):  
J. M. Rhoads ◽  
E. O. Keku ◽  
J. P. Woodard ◽  
S. I. Bangdiwala ◽  
J. G. Lecce ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Carbonic Acid ◽  
Apical Membrane ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Glutamine Metabolism ◽  
Nacl Absorption ◽  
The Relationship ◽  
Stimulation Of

To explore the relationship between intestinal fluid absorption and oxidative metabolism, we measured the effects of amino acids and glucose on piglet jejunal ion transport and oxygen consumption (QO2) in vitro. Jejunal QO2 was stimulated by L-glutamine and D-glucose but not by the nonmetabolizable organic solutes methyl beta-D-glucoside or L-phenylalanine. QO2 was maximally enhanced by the combination of D-glucose and L-glutamine (5 mM). Even though 5 mM L-glutamine was previously found to be insufficient to stimulate NaCl absorption, 5 mM L-glutamine enhanced jejunal NaCl flux when combined with equimolar mucosal D-glucose. Either D-glucose or methyl beta-D-glucoside caused an increase in short-circuit current (Isc), an increase in Na+ absorption in excess of Isc, and a decrease in Cl- secretion, when L-glutamine was substituted for D-glucose (10 mM) on the serosal side. This relationship suggests that mucosal sugars, if combined with L-glutamine, enhance neutral NaCl absorption as well as electrogenic Na+ flow. (Aminooxy)acetate, an inhibitor of alanine aminotransferase, abolished the stimulation of QO2 and the NaCl-absorptive response to L-glutamine. We conclude that the oxidative metabolism fueled by L-glutamine is linked to a NaCl-absorptive mechanism in the intestine. We propose that the CO2 produced by glutamine metabolism yields carbonic acid, which dissociates to H+ and HCO3-, which may stimulate parallel antiports in the apical membrane.

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