The 1986 Borden Award Lecture. The role of the kidney in amino acid metabolism and nutrition

1987 ◽  
Vol 65 (12) ◽  
pp. 2355-2362 ◽  
Author(s):  
John T. Brosnan
Keyword(s):  
Proximal Tubule ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Acid Metabolism ◽  
Rat Kidney ◽  
High Protein Diet ◽  
Serine Hydroxymethyltransferase ◽  
Glutamine Metabolism ◽  
Cleavage Enzyme ◽  
Glycine Cleavage

Measurement of the arteriovenous differences for free amino acids across rat kidney reveals that glycine and citrulline are removed and serine and arginine are added to the circulation. In addition, glutamine is taken up in large quantities by kidneys of animals that need to excrete large quantities of acid (e.g., diabetic animals, NH4Cl-fed animals, and animals fed a high protein diet). Glutamine is the major precursor of urinary ammonia and thus renal glutamine metabolism plays a key role in acid–base homeostasis. This process occurs primarily in the cells of the convoluted proximal tubule. Glutamine carbon is converted to glucose in acidotic rats and is totally oxidized in dogs. Regulation of glutamine metabolism occurs at two levels: acute regulation and chronic regulation. Acute regulation is, in part, mediated through a fall in intracellular [H+]. This activates α-ketoglutarate dehydrogenase and, ultimately, glutaminase. Chronic regulation involves induction of key enzymes, including, in the rat, glutaminase, glutamate dehydrogenase, and phosphoenolpyruvate carboxykinase. During the acidosis of prolonged starvation, the kidneys' requirement for glutamine must be met from muscle proteolysis and thus becomes a drain on lean body mass. Serine synthesis occurs by two separate pathways: from glycine by the combined actions of the glycine cleavage enzyme and serine hydroxymethyltransferase and from gluconeogenic precursors using the phosphorylated-intermediate pathway. Both pathways are located in the cells of the proximal tubule. Conversion of glycine to serine is ammoniagenic and the activity of the glycine cleavage enzyme is increased in acidosis. The function of serine synthesis by the phosphorylated-intermediate pathway is not apparent. Renal serine synthesis is quantitatively important; in man it is comparable to the serine obtained in the diet. Nevertheless, renal serine synthesis was not sensitive to serine status in rats as neither removal of dietary serine nor supplementation of the diet with serine affected renal serine synthesis. Arginine synthesis occurs from citrulline removed from the circulation. The citrulline is produced in the intestine. The kidney is the major endogenous source of arginine.

Serine synthesis in rat kidney: studies with perfused kidney and cortical tubules

1986 ◽  
Vol 250 (4) ◽  
pp. F649-F658
Author(s):  
M. Lowry ◽  
D. E. Hall ◽  
J. T. Brosnan
Keyword(s):  
Proximal Tubule ◽  
Rat Kidney ◽  
Distal Tubule ◽  
Serine Hydroxymethyltransferase ◽  
Percoll Gradient ◽  
Tight Coupling ◽  
Cleavage Enzyme ◽  
14Co2 Production ◽  
Glycine Cleavage ◽  
Perfused Kidney

Renal serine synthesis was studied in the isolated perfused kidney and in isolated cortical tubules. Serine was produced by the perfused kidney from both glycine and aspartate, indicating flux through at least two separate pathways: serine hydroxymethyltransferase and either the nonphosphorylated or phosphorylated intermediate pathways. The precise nephron site of serine production was determined by measuring serine synthesis from various precursors and the activities of enzymes of both pathways in isolated tubules fractionated on a Percoll gradient into proximal tubule and distal tubule fractions. Both pathways of serine synthesis were located in proximal tubules. Detailed studies of serine synthesis from glycine demonstrated extremely tight coupling between the glycine cleavage enzyme and serine hydroxymethyltransferase, since the rate of 14CO2 production from [2-14C]glycine was less than 5% of that of [1-14C]glycine, whereas the rate of incorporation of 14C into serine from [2-14C]glycine was double that from [1-14C]glycine. These studies demonstrate that the kidney can synthesize serine by two separate pathways, both located in the cells of the proximal tubule.

scholarly journals The role of phosphoenolpyruvate carboxykinase in amino acid metabolism in muscle

1978 ◽  
Vol 176 (2) ◽  
pp. 623-626 ◽  
Author(s):  
E A Newsholme ◽  
T Williams
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Malate Dehydrogenase ◽  
Amino Acid Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Acid Metabolism ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet

Starvation or feeding rats on a high-protein diet, valine or isoleucine, but not leucine, increases the activity of muscle phosphoenolpyruvate carboxykinase, but has no effect on NADP+-linked malate dehydrogenase. This suggests that muscle phosphoenolpyruvate carboxykinase is involved in oxidation or conversion of some amino acids to alanine.

Role of luminal hydrostatic pressure in proximal tubular fluid reabsorption in the rat

1975 ◽  
Vol 229 (3) ◽  
pp. 813-819 ◽  
Author(s):  
A Grandchamp ◽  
Scherrer ◽  
D Scholer ◽  
J Bornand
Keyword(s):  
Hydrostatic Pressure ◽  
Proximal Tubule ◽  
Pressure Difference ◽  
Unit Area ◽  
Rat Kidney ◽  
Fluid Reabsorption ◽  
Proximal Tubular ◽  
Tubular Fluid Reabsorption ◽  
Selective Change

The effect of small changes in intraluminal hydrostatic pressure (P) on the tubular radius (r) and the net fluid reabsorption per unit of surface area of the tubular wall (Js) has been studied in the proximal tubule of the rat kidney. The split-drop method was used to simultaneously determine Js and r. Two standardized split-drop techniques A and B allow selective change in P. P was 31.6 +/- 1.3 mmHg in technique A and 15.5 +/- 1.5 in technique B. The pressure difference significantly affected the tubular radius; r was 21.9 +/- 0.4 and 18.6 +/- 0.5 mum in the split drop A and B, respectively. In contrast, net transepithelial fluid reabsorption Js was unchanged. Js amounted to 2.72 +/- 0.20, and 2.78 +/- 0.33 10(-5) cm3 cm-2 s-1 in split drop A and B. The absence of variations in Js could result from two opposite effects of pressure. P might enhance Js by increased ultrafiltration. However, the rise in r might decrease the density of the intraepithelial transport paths per unit area of tubular wall and therefore might decrease Js.

Changes in mRNAs for enzymes of glutamine metabolism in kidney and liver during ammonium chloride acidosis

1994 ◽  
Vol 267 (3) ◽  
pp. F400-F406 ◽  
Author(s):  
A. C. Schoolwerth ◽  
P. A. deBoer ◽  
A. F. Moorman ◽  
W. H. Lamers
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Rat Kidney ◽  
Glutamine Metabolism ◽  
Kidney Cortex ◽  
Mrna Levels ◽  
Rat Kidney Cortex ◽  
Physiological Conditions ◽  
Glutamine Synthase ◽  
Sustained Increase

Changes in protein and mRNAs for enzymes of glutamine metabolism were determined in rat kidney cortex at different times after induction of NH4Cl acidosis. After NH4Cl, phosphoenolpyruvate carboxykinase (PEPCK) mRNA increased 16-fold by 10 h (P < 0.05) and then returned to control levels by 30 h. In situ hybridization (ISH) showed that PEPCK mRNA was confined to medullary rays; after NH4Cl, expression of PEPCK expanded throughout the cortex, reaching a maximal intensity at 10 h. Phosphate-dependent glutaminase (PDG) and glutamate dehydrogenase (GDH) mRNAs increased 8- and 2.6-fold, respectively (both P < 0.05), by 10 h before decreasing; the increased expression was confirmed by ISH. Immunohistochemistry showed that increased PEPCK, PDG, and GDH protein occurred at variable times after the rise in mRNAs. The increase was confined to proximal tubules and was sustained, a finding noted also by Western blot analysis. In contrast, glutamine synthase protein and mRNA, confined to deep cortex and outer medullar, did not change after NH4Cl. These studies reveal striking changes in PEPCK and PDG mRNAs in rat renal cortex during acidosis. The ISH pattern suggested that increased amounts of PEPCK were synthesized in recruited cells which contained little enzyme under physiological conditions. mRNA levels for PEPCK, PDG, and GDH peaked at 10 h before returning to control levels. Despite the decrease in mRNAs, a sustained increase in proteins was noted.

Role of NHE isoforms in mediating bicarbonate reabsorption along the nephron

2001 ◽  
Vol 281 (6) ◽  
pp. F1117-F1122 ◽  
Author(s):  
Tong Wang ◽  
Max Hropot ◽  
Peter S. Aronson ◽  
Gerhard Giebisch
Keyword(s):  
Proximal Tubule ◽  
Functional Role ◽  
Apical Membrane ◽  
Rat Kidney ◽  
Significant Inhibition ◽  
Distal Convoluted Tubule ◽  
Loop Of Henle ◽  
Nhe Isoforms

This study assessed the functional role of Na+/H+ exchanger (NHE) isoforms NHE3 and NHE2 in the proximal tubule, loop of Henle, and distal convoluted tubule of the rat kidney by comparing sensitivity of transport to inhibition by Hoe-694 (an agent known to inhibit NHE2 but not NHE3) and S-3226 (an agent with much higher affinity for NHE3 than NHE2). Rates of transport of fluid ( J v) and HCO[Formula: see text]( J HCO3) were studied by in situ microperfusion. In the proximal tubule, addition of ethylisopropylamiloride or S-3226 significantly reduced J v and J HCO3, but addition of Hoe-694 caused no significant inhibition. In the loop of Henle, J HCO3 was also inhibited by S-3226 and not by Hoe-694, although much higher concentrations of S-3226 were required than what was necessary to inhibit transport in the proximal tubule. In contrast, in the distal convoluted tubule, J HCO3was inhibited by Hoe-694 but not by S-3226. These results are consistent with the conclusion that NHE2 rather than NHE3 is the predominant isoform responsible for apical membrane Na+/H+ exchange in the distal convoluted tubule, whereas NHE3 is the predominant apical isoform in the proximal tubule and possibly also in the loop of Henle.

ORGANIC ACID METABOLISM IN GRAPE: ROLE OF PHOSPHOENOLPYRUVATE CARBOXYKINASE

2007 ◽  
pp. 599-602 ◽  
Author(s):  
F. Famiani ◽  
V. Casulli ◽  
P. Proietti ◽  
R.P. Walker ◽  
A. Battistelli
Keyword(s):  
Organic Acid ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Acid Metabolism ◽  
Organic Acid Metabolism

Regulation of sodium transporters in the thick ascending limb of rat kidney: response to angiotensin II

2003 ◽  
Vol 285 (1) ◽  
pp. F152-F165 ◽  
Author(s):  
Tae-Hwan Kwon ◽  
Jakob Nielsen ◽  
Young-Hee Kim ◽  
Mark A. Knepper ◽  
Jørgen Frøkiær ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Brush Border ◽  
Rat Kidney ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Outer Medulla ◽  
Protein Protein Interaction ◽  
Sodium Transporters ◽  
Outer Strip

The effect of ANG II treatment of rats for 7 days was examined with respect to the abundance and subcellular localization of key thick ascending limb (TAL) Na+ transporters. Rats were on a fixed intake of Na+ and water and treated with 0, 12.5, 25, 50 (ANG II-50), 100 (ANG II-100), and 200 (ANG II-200) ng·min-1·kg-1 ANG II (sc). Semiquantitative immunoblotting revealed that Na+/H+ exchanger 3 (NHE3) abundance in the inner stripe of the outer medulla (ISOM) of ANG II-treated rats was significantly increased: 179 ± 28 (ANG II-50, n = 5), 166 ± 23 (ANG II-100, n = 7), and 167 ± 19% (ANG II-200, n = 4) of control levels ( n = 6, P < 0.05), whereas lower doses of ANG II were ineffective. The abundance of the bumetanide-sensitive Na+-K+-2Cl- cotransporter (BSC-1) in the ISOM was also increased to 187 ± 28 (ANG II-50), 162 ± 23 (ANG II-100), and 166 ± 19% (ANG II-200) of control levels ( P < 0.05), but there were no changes in the abundance of Na+-K+-ATPase and the electroneutral Na+-HCO3 cotransporter NBCn1. Immunocytochemistry confirmed the increase in NHE3 and BSC-1 labeling in medullary TAL (mTAL). In the cortex and the outer strip of the outer medulla, NHE3 abundance was unchanged, whereas immunocytochemistry revealed markedly increased NHE3 labeling of the proximal tubule brush border, suggesting subcellular redistribution of NHE3 or differential protein-protein interaction. Despite this, ANG II-treated rats (50 ng·min-1·kg-1 for 5 days, n = 6) had a higher urinary pH compared with controls. NH4Cl loading completely blocked all effects of ANG II infusion on NHE3 and BSC-1, suggesting a potential role of pH as a mediator of these effects. In conclusion, increased abundance of NHE3 and BSC-1 in mTAL cells as well as increased NHE3 in the proximal tubule brush border may contribute to enhanced renal Na+ and HCO3 reabsorption in response to ANG II.

Strychnine Therapy in Nonketotic Hyperglycinemia

PEDIATRICS ◽  
1979 ◽  
Vol 63 (3) ◽  
pp. 369-373
Author(s):  
Dora Arneson ◽  
Lawrence T. Ch'ien ◽  
Philip Chance ◽  
R. Sidney Wilroy
Keyword(s):  
Sodium Benzoate ◽  
Inborn Error ◽  
Enzyme System ◽  
Inhibitory Neurotransmitter ◽  
Patient Reported ◽  
Cleavage Enzyme ◽  
Specific Antagonist ◽  
Glycine Cleavage ◽  
Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is an inborn error of metabolism resulting from a defect in the glycine cleavage enzyme system. It is characterized biochemically by elevated concentrations of glycine in blood, spinal fluid, and urine. Previous therapies which have been directed toward reducing the glycine concentration in plasma and CSF have not been successful in preventing neurological deterioration, which may be the result of the role of glycine as an inhibitory neurotransmitter. Strychnine treatment was initiated because it is a specific antagonist of glycine at postsynaptic membranes. The patient reported here has shown clinical and EEG improvement while taking strychnine in conjunction with sodium benzoate.

Distribution along the rat nephron of three enzymes of gluconeogenesis in acidosis and starvation

1978 ◽  
Vol 235 (3) ◽  
pp. F246-F253 ◽  
Author(s):  
H. B. Burch ◽  
R. G. Narins ◽  
C. Chu ◽  
S. Fagioli ◽  
S. Choi ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Rat Kidney ◽  
Proximal Convoluted Tubule ◽  
Straight Segment ◽  
Straight Tubule ◽  
Freeze Dried ◽  
Fructose 1,6 Bisphosphatase ◽  
Straight Portion

Methods were devised or modified which made it possible to measure phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase in seven defined parts of single nephrons and in patches from thin limb and papilla areas dissected from freeze-dried microtome sections of rat kidney. All three enzymes were essentially confined to the proximal tubule. In normal kidneys, the levels were highest in the proximal convoluted tubule. Glucose-6-phosphatase was 20 times higher in the early part of the convoluted segment than in the late part of the straight segment. With one exception, in acidosis, only phosphoenolpyruvate carboxykinase increased (fourfold in the proximal convoluted segment but much less in the straight portion). In starvation, phosphoenolpyruvate carboxykinase increased about as much as in acidosis in the proximal straight tubule, but not as much in convoluted portions, whereas glucose-6-phosphatase rose modestly in both parts of the proximal tubule and fructose bisphosphatase rose only in the straight tubule, especially the early segment. It is suggested that ammoniagenesis can accompany gluconeogenesis in the proximal convoluted tubule but not in the straight segment.

Renal glutamine metabolism in rats fed high-protein diets.

1978 ◽  
Vol 235 (3) ◽  
pp. E261 ◽  
Author(s):  
J T Brosnan ◽  
P McPhee ◽  
B Hall ◽  
D M Parry
Keyword(s):  
Protein Intake ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Sodium Bicarbonate Solution ◽  
Ammonia Excretion ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Glutamine Metabolism ◽  
High Protein Diets ◽  
Protein Diets

The influence of protein intake on acid excretion and renal glutamine metabolism was investigated and compared to the effects of NH4Cl-induced metabolic acidosis. Rats fed a diet containing 55% casein excreted more ammonia, phosphate, sulphate, and chloride than did rats fed a 13% casein diet, but, when they were given an 0.1 M NaHCO3 solution to drink, ammonia excretion was no longer elevated. Renal phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase activities, ammoniagenesis by isolated mitochondria, and the rate of renal gluconeogenesis were all elevated in the rats fed the high-protein diet but not if these rats also drank the sodium bicarbonate solution. Increased glutaminase and phosphoenolpyruvate carboxykinase activities, mitochondrial ammoniagenesis, and gluconeogenesis were all evident in rats made acidotic with NH4Cl. It is concluded that these metabolic adaptations evident in the kidneys of rats fed the high-protein diet are due to the acidogenic effects of increased protein intake.

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