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Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870
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ABSTRACT |
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 TOP ABSTRACT Renal glutamine metabolismAcute acidosisChronic acidosisProperties of the mitochondrial...Stabilization of GA mRNALITERATURE CITED |
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-ketoglutarate is further metabolized to
phosphoenolpyruvate and subsequently to glucose or
CO2. The intermediate steps yield two bicarbonate ions that
are selectively transported into the venous blood to partially
compensate the metabolic acidosis. In rat kidney, this adaptation is
sustained in part by the cell-specific induction of the glutaminase
that results primarily from stabilization of the GA mRNA. The
3'-nontranslated region of the GA mRNA contains a direct repeat of an
8-base AU-sequence that functions as a pH-response element.
This sequence exhibits a high affinity and specificity for zeta
(z)-crystallin. The same protein binds to two separate, but homologous,
8-base AU-sequences within the 3'-nontranslated region of the GDH
mRNA. The apparent binding activity of z-crystallin is increased
significantly during onset of metabolic acidosis. Thus, increased
binding of z-crystallin may initiate the pH-responsive
stabilization of the two mRNAs.
KEY WORDS: • glutamine • glutamate dehydrogenase • zeta-crystallin • renal ammoniagenesis
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Renal glutamine metabolism |
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TOPABSTRACTRenal glutamine metabolismAcute acidosisChronic acidosisProperties of the mitochondrial...Stabilization of GA mRNALITERATURE CITED |
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). The
measured renal arterial-venous difference for plasma glutamine is
normally < 0.03. However, 
20% of the plasma glutamine is
filtered by the glomeruli and enters the lumen of the nephron. The
filtered glutamine is reabsorbed primarily by the epithelial cells of
the proximal convoluted tubule (Silbernagl 1980
). The
glutamine is initially transported across the apical brush border
membrane, and subsequently, most of the recovered glutamine is returned
to the blood via transport across the basolateral membrane. The
specific transporters that are responsible for the transcellular flux
of glutamine have not been identified.
Utilization of the small fraction of extracted plasma glutamine
requires its transport into the mitochondrial matrix where glutamine is
deamidated by glutaminase
(GA)3
and then oxidatively deaminated by glutamate dehydrogenase (GDH).
Glutamine uptake occurs via a mersalyl-sensitive electroneutral
uniporter (Sastrasinh and Sastrasinh 1989
). The
mitochondrial glutamine transporter was recently purified from rat
kidney and shown by reconstitution in lipid vesicles to be specific for
glutamine and asparagine and inhibited by various thiol reagents
(Indiveri et al. 1998
). Kinetic measurements indicated
that the rate of glutamine transport in isolated rat renal mitochondria
is not rate limiting for glutamine catabolism (Goldstein and Boylan 1978
, Kovacevic and Bajin 1982
). However,
either the activity of the mitochondrial glutamine transporter or the
glutaminase must be largely inactivated in vivo during normal
acid-base balance to account for the effective reabsorption of
glutamine. During normal acid-base balance, approximately two
thirds of the ammonium ions produced from glutamine are trapped in the
tubular lumen and excreted in a slightly acidified urine.
Rat kidney also expresses significant levels of
-glutamyltranspeptidase, an enzyme that catalyzes a
phosphate-independent glutaminase activity (Curthoys and Kuhlenschmidt 1975
). However, this enzyme is localized
primarily to the brush border membrane of the proximal straight tubules
(Curthoys and Lowry 1973
), a site that is distal to the
recovery of the filtered glutamine. Furthermore, the in vivo inhibition
of -glutamyltranspeptidase (Scott and Curthoys 1987
)
causes a pronounced glutathioneuria, but has little effect on renal
ammoniagenesis. Thus, this enzyme functions primarily to degrade
filtered and secreted glutathione (Curthoys 1983
) and is
unlikely to contribute significantly to the renal catabolism of
glutamine.
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Acute acidosis |
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TOPABSTRACTRenal glutamine metabolismAcute acidosisChronic acidosisProperties of the mitochondrial...Stabilization of GA mRNALITERATURE CITED |
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). Thus, the renal catabolism of
glutamine is rapidly activated after the acute onset of metabolic
acidosis (Fig. 1
). Within 1–3 h, the arterial plasma glutamine concentration is
increased twofold (Hughey et al. 1980
) due primarily to
an increased release of glutamine from muscle tissue (Schrock et al. 1980
). Significant renal extraction of glutamine becomes
evident as the arterial plasma concentration is increased. Net
extraction reaches 30% of the plasma glutamine, a level that exceeds
the percentage filtered by the glomeruli. Thus, the direction of the
basolateral glutamine transport must be reversed for the proximal
convoluted tubule cells to extract glutamine from both the glomerular
filtrate and the venous blood. In addition, the transport of glutamine
into the mitochondria may be acutely activated. Further responses
include a prompt acidification of the urine that results from an acute
activation of the apical
Na+/H+ antiporter activity
(Horie et al. 1990
). This process facilitates the rapid
removal of cellular ammonium ions (Tannen and Ross 1979
)
and ensures that the bulk of the ammonium ions generated in the
proximal tubule are excreted in the urine. Finally, a pH-induced
activation of -ketoglutarate dehydrogenase reduces the intracellular
concentrations of -ketoglutarate and glutamate (Lowry and Ross 1980
). Thus, increased catabolism initially results from a
rapid activation of key transport processes, an increased availability
of glutamine, and a decreased concentration of the products of the
glutaminase and glutamate dehydrogenase reactions.
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Chronic acidosis |
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TOPABSTRACTRenal glutamine metabolismAcute acidosisChronic acidosisProperties of the mitochondrial...Stabilization of GA mRNALITERATURE CITED |
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). However, the kidney continues to extract more than one
third of the total plasma glutamine (Squires et al. 1976
) in a single pass through this organ (Fig. 2
). Renal catabolism of glutamine is now sustained by increased
expression of the genes that encode the mitochondrial glutaminase
(Curthoys and Lowry 1973
) and glutamate dehydrogenase
(Wright and Knepper 1990a
), the cytoplasmic
phosphoenolpyruvate carboxykinase (PEPCK) (Burch et al. 1978
), and the mitochondrial glutamine, the apical
Na+/H+ and the basolateral
Na+-3HCO3- transport
systems (Preisig and Alpern 1988
). All of these
adaptations occur solely within the renal proximal convoluted tubule.
The coordinate increase in enzyme activities facilitates the continued
catabolism of glutamine. The concomitant increase in the apical
Na+/H+ antiporter activity
sustains the acidification of the fluid in the tubular lumen and
ensures the urinary excretion of the ammonium ions. Thus, the increased
renal ammoniagenesis continues to provide an expendable cation that
facilitates the excretion of titratable acids while conserving sodium
and potassium ions. The increased
Na+/H+ antiporter activity
also promotes the tubular reabsorption of HCO3-
ions. In addition, the -ketoglutarate generated from glutamine is
converted to glucose. This process generates 2 mol of
HCO3- ions per mole of -ketoglutarate. An
increase in the basolateral
Na+-3HCO3- cotransporter
activity facilitates the translocation of reabsorbed and de novo
synthesized HCO3- ions into the renal venous
blood. Thus, the combined adaptations also create a net renal release
of HCO3- ions, which partially compensate the
systemic acidosis.
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Properties of the mitochondrial glutaminase |
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TOPABSTRACTRenal glutamine metabolismAcute acidosisChronic acidosisProperties of the mitochondrial...Stabilization of GA mRNALITERATURE CITED |
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). Within
24 h after the onset of acidosis, the glutaminase activity is
increased twofold within the proximal convoluted tubule. However, due
to the cell specificity of the increase and the greater level of
activity associated with distal tubules, 2–3 d are required to observe
a significant increase in glutaminase activity in crude homogenates of
whole kidney. The total renal glutaminase activity increases gradually
and eventually reaches a plateau after 7 d of acidosis at a value
that is four- to fivefold greater than normal. The maximal induction is
due to a 7- to 20-fold increase within the proximal convoluted tubule
(Curthoys and Lowry 1973
, Wright and Knepper 1990b
).
Immunologic experiments have established that the increase in renal
glutaminase activity is due to the presence of an increased amount of
protein and not to an activation of preexisting enzyme (Curthoys et al. 1976
). The relative rate of renal synthesis of
glutaminase was determined by pulse-labeling experiments
(Tong et al. 1986
). After the onset of acidosis, the
relative rate of glutaminase synthesis increased gradually and reached
a plateau within 5 d at a value that was 5.3-fold greater than
normal. The apparent half-lives for glutaminase degradation
measured in normal and acidotic rats were nearly identical. Thus, the
stimulation of glutaminase synthesis accounts for the fivefold increase
in glutaminase activity. Acute recovery from chronic acidosis causes a
rapid decrease in the relative rate of glutaminase synthesis and in
renal ammoniagenesis. However, the level of glutaminase activity
decreases gradually and requires 10–12 d to return to normal
(Parry and Brosnan 1978
). Therefore, the in vivo flux
through the glutaminase must be inhibited either by inactivating the
mitochondrial glutamine transporter or by altering the matrix
concentrations of specific activators and/or inhibitors of the
glutaminase.
To further characterize the mechanism responsible for the adaptive
increase in renal glutaminase activity, the changes in the relative
levels of translatable GA mRNA were determined (Tong et al. 1987
). The relative levels of translatable GA mRNA increased
gradually and required 7 d to reach a maximal induction of
4.2-fold. At all times, the changes in relative level of translatable
GA mRNA correlated well with the previously observed changes in the
relative rate of glutaminase synthesis. Therefore, induction of the
mitochondrial glutaminase is not due to stimulation of the
translocation and processing of its precursor or to the regulation of a
required post-translational modification.
A GA cDNA hybridizes to 4.7- and 3.4-kb mRNAs that are contained in
total or polyA+ RNA isolated from rat kidney. The
levels of the two mRNAs are coordinately affected in response to
changes in acid-base balance (Hwang and Curthoys 1991
, Hwang et al. 1991
). During onset of acute
acidosis, increases in the two GA mRNAs are initiated after a 6- to 8-h
lag, and they reach a plateau within 16–18 h at levels that are
eightfold greater than normal. Acute recovery from chronic acidosis
also initiates a rapid and coordinate decrease in the levels of the two
GA mRNAs. The acute decrease occurs with first-order kinetics and
an apparent half-life of 4 h. The different kinetic profiles
suggest that the processes of induction and recovery may occur by
altering the stability of the GA mRNAs.
The proximal promoter region of the renal glutaminase gene lacks an
identifiable TATA box (Taylor et al. 2001
). Computer
analysis of the 2.3-kb promoter segment identified a number of putative
binding sites for known transcription factors that may contribute to
basal and activated transcription (Fig. 3
). However, nuclear run-on assays indicate that the rate of
transcription of the renal GA gene is unaffected by alterations in
acid-base balance (Hwang and Curthoys 1991
,
Hwang et al. 1991
). Thus, the increase in glutaminase
activity during chronic acidosis results from increased levels of total
and translatable GA mRNAs that apparently occur due to an increased
stability of the GA mRNA.
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Stabilization of GA mRNA |
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TOPABSTRACTRenal glutamine metabolismAcute acidosisChronic acidosisProperties of the mitochondrial...Stabilization of GA mRNALITERATURE CITED |
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) into
LLC-PK1-FBPase+ cells, a
pH-responsive porcine proximal tubule-like cell line
(Gstraunthaler and Handler 1987
). Expression of pßG
produced a high level of a very stable mRNA
(t1/2 > 30 h) that was not
affected by transfer of the cells to acidic medium (pH 6.9, 10 mmol
HCO3-). In contrast, pßG-GA, which encodes
an additional 956-base segment of the 3'-nontranslated region of the GA
mRNA, was expressed at significantly lower levels. The decreased
expression resulted from the more rapid turnover
(t1/2 = 4.6 h) of the ßG-GA
mRNA. Transfer of the latter cells to acidic medium resulted in a
pronounced stabilization (sixfold) and a gradual induction of the
ßG-GA mRNA. These studies indicated that the 3'-nontranslated region
of the GA mRNA contains a pH-response element (pH-RE).
Experiments using additional chimeric ßG constructs indicated that a
340-base segment of the GA mRNA, termed R-2, retained most of the
functional characteristics of the 3'-nontranslated region
(Laterza et al. 1997
). Mapping studies, using RNA
gel-shift assays, demonstrated that the specific binding site
within the R-2 RNA consisted of a direct repeat of an 8-base
AU-sequence. Site-directed mutation of the direct repeat of the
8-base AU-sequence completely abolished the pH-responsive
stabilization of the ßG-GA mRNA (Laterza and Curthoys 2000a
). A ßG reporter construct that contained the
3'-nontranslated region of the PEPCK mRNA, pßG-PCK, was designed to
further test the function of the AU-element. When expressed in
LLC-PK1-FBPase+ cells, the
half-life of the ßG-PCK mRNA was only slightly stabilized
(1.3-fold) by growth in acidic medium. However, insertion of short
segments of GA cDNA containing either the direct repeat or a single
8-base AU-sequence was sufficient to impart a fivefold
pH-responsive stabilization to the chimeric mRNA. Thus, either the
direct repeat or a single copy of the 8-base AU-sequence is both
necessary and sufficient to function as a pH-RE.
The apparent binding to the pH-RE is increased threefold in
cytosolic extracts prepared from
LLC-PK1-FBPase+ cells that
were grown in acidic medium (Laterza and Curthoys 2000b
). Extracts prepared from the renal cortex of rats that
were made acutely acidotic also exhibit a similar increase in binding
to the direct repeat of the pH-RE. The time course for the increase
in binding correlates with the temporal increase in GA mRNA. Scatchard
analysis indicates that the increased binding is due to an increase in
both the affinity and the maximal binding of the pH-RE binding
protein.
A biotinylated oligoribonucleotide containing the pH-RE was used as
an affinity ligand to purify a 36-kDa protein from rat renal cortex
(Tang and Curthoys 2001
). The isolated protein retained
the same specific binding properties as observed with crude cytosolic
extracts. Microsequencing of the purified protein by mass spectroscopy
yielded eight peptides that are contained in mouse zeta (z)-crystallin.
In addition, three peptides that differed by a single amino acid from
sequences found in mouse z-crystallin were identified. The observed
differences may represent substitutions found in the rat homolog.
Specific antibodies to z-crystallin supershifted the complex formed
between the pH-RE and the purified protein. The 3'-nontranslated
region of the GDH mRNA contains four 8-base AU-rich segments in
which 7 of the 8 bases are identical to the pH-RE sequence
identified in the GA mRNA. The purified z-crystallin binds to two
of these sequences with high affinity and specificity (Schroeder and
Curthoys, unpublished data). Thus, increased binding of
z-crystallin to the GA and GDH mRNAs may initiate their
stabilization and increased expression during acidosis.
The cumulative data are consistent with the following model (Fig. 4
). In normal acid-base balance, the pH-RE present in the
3'-nontranslated region of the GA mRNA recruits a site-specific
endoribonuclease. The onset of metabolic acidosis causes an increase in
the binding affinity of z-crystallin for the pH-RE. This, in
turn, confers increased protection to the GA mRNA from endonucleolytic
cleavage and results in an increased stabilization of the GA mRNA. This
hypothesis represents the simplest interpretation of the available
data. However, the current data do not rule out more complex
mechanisms. Further characterization of the actual mechanism will be
facilitated through the development of in vitro mRNA decay assays and
the use of recombinant z-crystallin.
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FOOTNOTES |
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2 Supported in part by Grants DK-37124 and
DK-43704 from the National Institute of Diabetes and Digestive and
Kidney Diseases.
3 Abbreviations used: GA, glutaminase; GDH,
glutamate dehydrogenase; PEPCK, phosphoenol pyruvate
carboxykinase; ßG, ß-globin; pH-RE, pH-response element; z,
zeta.
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LITERATURE CITED |
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TOPABSTRACTRenal glutamine metabolismAcute acidosisChronic acidosisProperties of the mitochondrial...Stabilization of GA mRNALITERATURE CITED |
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1. Brosnan J. T., Vinay P., Gougoux A. & Halperin M. L. (1988) Renal ammonia production and its implications for acid-base balance. Häussinger D. eds. pH Homeostasis-Mechanism and Control 1988:281-304 Academic Press New York, NY. .
2.
Burch H. B., Narins C., Chu C., Fagiolo S., Choi S., McCarthy W. & Lowry O. H. (1978) Distribution along the rat nephron of three enzymes of gluconeogenesis in acidosis and starvation. Am. J. Physiol. 235:F246-F253.
3.
Curthoys N. P. (1983) Role of -glutamyltranspeptidase in renal metabolism of glutathione. Miner. Electrolyte Metab. 9:236-245.[Medline]
4.
Curthoys N. P. & Kuhlenschmidt T. (1975) Phosphate-independent glutaminase from rat kidney: partial purification and identity with -glutamyltranspeptidase. J. Biol. Chem. 250:2099-2105.
5. Curthoys N. P., Kuhlenschmidt T., Godfrey S. S. & Weiss R. F. (1976) Phosphate-dependent glutaminase from rat kidney. Cause of increased activity in response to acidosis and identity with glutaminases from other tissues. Arch. Biochem. Biophys. 172:162-167.[Medline]
6.
Curthoys N. P. & Lowry O. H. (1973) The distribution of glutaminase isoenzymes in the various structures of the nephron in normal, acidotic and alkalotic rat kidney. J. Biol. Chem. 248:162-168.
7. Goldstein L. & Boylan J. M. (1978) Renal mitochondrial glutamine transport and metabolism: studies with a rapid-mixing, rapid-filtration technique. Am. J. Physiol. 234:F514-F521.
8.
Gstraunthaler G. & Handler J. S. (1987) Isolation, growth and characterization of a gluconeogenic strain of renal cells. Am. J. Physiol. 252:C232-C238.
9.
Hansen W. R., Barsic-Tress N., Taylor L. & Curthoys N. P. (1996) The 3'-nontranslated region of the rat renal glutaminase mRNA contains a pH-responsive stability element. Am. J. Physiol. 271:F126-F131.
10.
Horie S., Moe O., Tejedor A. & Alpern R. J. (1990) Preincubation in acid medium increases Na/H antiporter activity in cultured renal proximal tubule cells. Proc. Natl. Acad. Sci. U.S.A. 87:4742-4745.
11. Hughey R. P., Rankin B. B. & Curthoys N. P. (1980) Acute acidosis and renal arteriovenous differences of glutamine in normal and adrenalectomized rats. Am. J. Physiol. 238:F199-F204.
12.
Hwang J.-J. & Curthoys N. P. (1991) Effect of acute alterations in acid-base balance on rat renal glutaminase and phosphoenolpyruvate carboxykinase gene expression. J. Biol. Chem. 266:9392-9396.
13. Hwang J.-J., Perera S., Shapiro R. A. & Curthoys N. P. (1991) Mechanism of altered renal glutaminase gene expression in response to chronic acidosis. Biochemistry 30:7522-7526.[Medline]
14. Indiveri C., Abruzzo G., Stipani I. & Palmieri F. (1998) Identification and purification of the reconstitutively active glutamine carrier from rat kidney mitochondria. Biochem. J. 333:285-290.
15. Kovacevic Z. & Bajin K. (1982) Kinetics of glutamine-efflux from liver mitochondria loaded with the 14C-labeled substrate. Biochim. Biophys. Acta 687:291-295.[Medline]
16. Laterza O. F. & Curthoys N. P. (2000a) Specificity and functional analysis of the pH-responsive element within renal glutaminase mRNA. Am. J. Physiol. 278:F970-F977.
17.
Laterza O. F. & Curthoys N. P. (2000b) Effect of acidosis on the properties of the glutaminase mRNA pH-response element binding protein. J. Am. Soc. Nephrol. 11:1583-1588.
18.
Laterza O. F., Hansen W. R., Taylor L. & Curthoys N. P. (1997) Identification of an mRNA-binding protein and the specific elements that may mediate the pH-responsive induction of renal glutaminase mRNA. J. Biol. Chem. 272:22481-22488.
19. Lowry M. & Ross B. D. (1980) Activation of oxoglutarate dehydrogenase in the kidney in response to acute acidosis. Biochem. J. 190:771-780.[Medline]
20. Parry D. M. & Brosnan J. T. (1978) Glutamine metabolism in the kidney during induction of, and recovery from, metabolic acidosis in the rat. Biochem. J. 174:387-396.[Medline]
21. Preisig P. A. & Alpern R. J. (1988) Chronic metabolic acidosis causes adaptation in the apical membrane Na/H antiporter and basolateral Na(HCO3)3 symporter in the rat proximal convoluted tubule. J. Clin. Investig. 82:1445-1453.
22.
Sastrasinh S. & Sastrasinh M. (1989) Glutamine transport in submitochondrial particles. Am. J. Physiol. 257:F1050-F1058.
23. Schrock H., Chu C. J. & Goldstein L. (1980) Glutamine release from hindlimb and uptake by kidney in the acutely acidotic rat. Biochem. J. 188:557-560.[Medline]
24.
Scott R. & Curthoys N. P. (1987) Renal clearance of glutathione measured in rats pretreated with inhibitors of gutathione metabolism. Am. J. Physiol. 252:F877-F882.
25. Silbernagl S. (1980) Tubular reabsorption of L-glutamine studied by free-flow micropuncture and microperfusion of rat kidney. Int. J. Biochem. 12:9-16.[Medline]
26. Squires E. J., Hall D. E. & Brosnan J. T. (1976) Arterovenous differences for amino acids and lactate across kidneys of normal and acidic rats. Biochem. J. 160:125-128.[Medline]
27.
Tang A. & Curthoys N. P. (2001) Identification of z-crystallin/NADPH: quinone reductase as a renal glutaminase mRNA pH-response element binding protein. J. Biol. Chem. 276:21375-21380.
28. Tannen R. L. & Ross B. D. (1979) Ammoniagenesis by the isolated perfused rat kidney: the critical role of urinary acidification. Clin. Sci. (Lond.) 56:353-364.[Medline]
29. Taylor L., Liu X., Newsome W., Shapiro R. A., Srinivasan M. & Curthoys N. P. (2001) Isolation and characterization of the promoter region of the rat kidney-type glutaminase gene. Biochem. Biophys. Acta 1515:132-136.
30. Tong J., Harrison G. & Curthoys N. P. (1986) The effect of metabolic acidosis on the synthesis and turnover of rat renal phosphate-dependent glutaminase. Biochem. J. 233:139-144.[Medline]
31. Tong J., Shapiro R. A. & Curthoys N. P. (1987) Changes in the levels of translatable glutaminase mRNA during onset and recovery from metabolic acidosis. Biochemistry 26:2773-2777.[Medline]
32.
Wright P. A. & Knepper M. A. (1990a) Glutamate dehydrogenase activities in microdissected rat nephron segments: effects of acid-base loading. Am. J. Physiol. 259:F53-F59.
33.
Wright P. A. & Knepper M. A. (1990b) Phosphate-dependent glutaminase activity in rat renal cortical and medullary tubule segments. Am. J. Physiol. 259:F961-F970.
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