1 Departments of Cellular and Molecular Physiology and 2 Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520
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ABSTRACT |
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Using
renal clearance techniques and in situ microperfusion of proximal
tubules, we examined the effects of
NG-monomethyl-L-arginine methyl
ester (L-NAME) on fluid and HCO3
transport in wild-type mice and also investigated proximal tubule transport in neuronal nitric oxide synthase (nNOS)-knockout mice. In
wild-type mice, administration of L-NAME (3 mg/kg bolus iv) significantly increased mean blood pressure, urine volume, and urinary
Na+ excretion. L-NAME, given by intravenous
bolus and added to the luminal perfusion solution, decreased absorption
of fluid (60%) and HCO3
(49%) in the proximal
tubule. In nNOS-knockout mice, the urinary excretion of
HCO3
was significantly higher than in the wild-type
mice (3.12 ± 0.52 vs. 1.40 ± 0.33 mM) and the rates of
HCO3
and fluid absorption were 62 and 72% lower,
respectively. Both arterial blood HCO3
concentration
(20.7 vs. 25.7 mM) and blood pH (7.27 vs. 7.34) were lower, indicating
a significant metabolic acidosis in nNOS-knockout mice. Blood pressure
was lower in nNOS-knockout mice (76.2 ± 4.6 mmHg) than in
wild-type control animals (102.9 ± 8.4 mmHg); however, it
increased in response to L-NAME (125.5 ± 5.07 mmHg).
Plasma Na+ and K+ were not significantly
different from control values. Our data show that a large component of
HCO3
and fluid absorption in the proximal tubule is
controlled by nNOS. Mice without this isozyme are defective in
absorption of fluid and HCO3
in the proximal tubule
and develop metabolic acidosis, suggesting that nNOS plays an important
role in the regulation of acid-base balance.
bicarbonate; acid-base
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INTRODUCTION |
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NITRIC OXIDE SYNTHASES (NOS) are a family of enzymes that synthesize nitric oxide (NO) from L-arginine in mammalian tissue. Three isoforms of NOS have been identified and defined according to the tissue in which they were discovered: they are present in neurons (nNOS), in endothelial cells (eNOS), and inducible in macrophages and hepatocytes (iNOS) (26, 33). In the kidney eNOS is expressed in renal vascular endothelial cells (36, 37) whereas nNOS is expressed predominantly in the tubule epithelium, Bowman's capsule, especially the macula densa (25, 28, 48), and in principal cells of the collecting duct (47). However, whether nNOS is expressed in the proximal tubule is not very clear. iNOS is widely expressed in the tubule epithelium, including the proximal tubule, thick ascending limbs of Henle's loop, and distal convoluted tubule (27, 37).
In previous microperfusion studies in rats, we have demonstrated that
blocking of NOS by
NG-monomethyl-L-arginine methyl
ester (L-NAME) significantly decreases, whereas luminal
application of NO donors such as sodium nitroprusside (SNP) and
S-nitroso-N-acetylpenicillamine (SNAP) increase
fluid and HCO3 absorption in the rat proximal tubule.
These findings indicate enhancement of fluid and HCO3
absorption by endogenous NO (40). Two important issues
remain unresolved. It is not been clear whether NO increases or
decreases HCO3
and Na+ transport under
physiological conditions, because both stimulation and inhibition of
tubule fluid transport have been reported (2, 9, 12, 30,
40). Second, although all three NOS isozymes are expressed in
the kidney (1, 3, 22, 36, 37), the physiological role of
each isozyme in the regulation of transport has not been defined
because selective inhibitors of NOS isozymes are not available. In the
present study we examined the effects of L-NAME on urine
volume and Na+ excretion and also on fluid and
HCO3
absorption in the proximal tubule in control
mice. Our data show that L-NAME significantly increased
urine volume and Na+ excretion and reduced the rate of
fluid and HCO3
absorption in the perfused proximal
tubules. However, because L-NAME is a nonspecific NOS
inhibitor, these results did not indicate which NOS isozyme(s) play(s)
a role in the regulation of fluid and HCO3
transport.
In the present study we measured the urinary excretion of
HCO3
in mice lacking nNOS, iNOS, and eNOS
individually. Because urinary excretion of HCO3
was
significantly higher in the nNOS- knockout mice compared with all other
groups, we examined the proximal tubule transport of fluid and
HCO3
in nNOS-knockout mice.
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METHODS |
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Animal preparation and surgical procedures.
C57 Black 6J mice were used for studying renal clearances and the
effects of L-NAME. Wild-type, iNOS-, and eNOS-knockout mice were obtained from Jackson Laboratory and used for the studies of urine
pH and HCO3. In addition, nNOS wild-type and knockout
mice were bred from mice provided by Dr. Paul Huang (Harvard
University, Boston, MA) (15). The mice were back-bred on a
C57 Black 6J background so that variability within the genetic
background of the mice was randomly distributed between (+/+) and
(
/
) mice (17). All animals were maintained on a
defined diet and tap water until the day of the experiment. The ages of
the nNOS
/
animals were matched with their wild-type controls.
Renal clearance.
Renal clearance studies in mice were carried out as described
previously (39, 43). On completion of surgery, 0.3% body wt of isotonic saline was given intravenously to replace surgical fluid
losses. Subsequently, a priming dose of 5 µCi of
[3H]methoxyinulin (New England Nuclear, Boston, MA) was
given in 0.05 ml isotonic saline followed by a maintenance infusion of 0.9% NaCl and 4 mM of KCl containing 10 µCi/ml of
[3H]inulin (infusion rate: 0.41 ml/h). An equilibration
period of 60 min was allowed before the experiment commenced. The
collection periods were 30 min. After two 30-min collection periods
L-NAME (3 mg/kg) was given by bolus intravenous (iv)
injection. A similar amount of saline was given in a control group.
Twenty-microliter blood samples were taken at the beginning and end of
each urine collection period. Blood pressure, urine volume, glomerular
filtration rate (GFR), absolute excretion rates of Na+ and
K+ (ENa, EK), fractional excretion
of Na+ and K+ (FENa,
FEK), and plasma Na+ and plasma K+
concentrations were determined. In addition, blood pH,
PCO2, and HCO3 concentrations
were measured by a blood-gas analyzer (Corning Medical and Scientific,
Corning, NY). Na+ and K+ concentrations in
plasma and urine were measured by standard flame photometry (type 480 flame photometer, Corning Medical and Scientific), and absolute and
fractional renal excretion rates were calculated by standard methods
(45).
Microperfusion of proximal tubule in vivo. Microperfusion of superficial proximal tubules in vivo was performed by a method similar to that described previously (46). After surgical preparation, the animal was placed on a thermostatically controlled surgical table, and body temperature was maintained at 37°C. Saline solution (0.9%) was infused at a rate of 0.15 ml/h. The left kidney was exposed through a lateral abdominal incision and carefully isolated and immobilized in a kidney cup filled with light mineral oil (37°C). The kidney surface was illuminated by a fiber-optic light. A proximal convoluted tubule with three to five loops on the kidney surface was selected and perfused with a Hampel-type microperfusion pump at a rate of 15 nl/min with a proximal oil block. Tubule fluid collections were made downstream by using another micropipette with a distal side oil block.
The composition of the perfusion fluids was as follows (in mM): 115 NaCl, 24 NaHCO3, 4 KCl, 1 CaCl2, 5 Na-acetate, 5 glucose, 5 L-alanine, 2.5 Na2HPO4, and 0.5 NaH2PO4. The solution was bubbled at room temperature with 5% CO2-95% O2 before use. pH was adjusted to 7.4 with a small amount of NaOH or HCl as required. The perfusion solutions also contained 20 µCi/ml of low-sodium [3H]methoxyinulin for measuring volume absorption and 0.1% FD & C green dye for identification of the perfused loops. After perfusion fluid collections, the perfused tubules were marked with heavy mineral oil stained with Sudan black. To determine the length of the perfused segment, tubules were filled with high-viscosity microfil (Canton Bio-Medical Products, Boulder, CO), the kidney was partially digested in 20% NaOH, and silicone rubber casts of the tubule segments were dissected.Measurement of rate of volume and HCO3
absorption.
The fluid volumes of the original and collected samples were measured
in constant-bore glass capillary tubes. The concentration of
radioactive [3H]methoxyinulin contained within each
sample was determined by liquid scintillation spectroscopy. The rate of
net fluid reabsorption (Jv) was calculated
according to the [3H]inulin concentration changes between
the original and collected fluid.
Statistics. Control and experimental groups were studied under identical experimental conditions. Data are presented as means ± SE. Student's t-test was used to compare control and experimental groups. One-way ANOVA and Dunnett's test were used for comparison of several experimental groups with a control group. The difference between the mean values of an experimental group and a control group was considered significant at P < 0.05.
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RESULTS |
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Effects of L-NAME on renal clearance.
The effects of one dose of L-NAME (3 mg/kg) bolus iv on
MAP, GFR, and urine volume are summarized in Fig.
1. The top left panel shows that the baseline of MAP is not significantly different between the control and experimental group before L-NAME
administration; however, MAP increased by 28, 26, and 19%,
respectively, 30, 60, and 90 min after L-NAME injection,
and the average MAP was significantly higher in the L-NAME
group. The middle left panel shows that GFR increased slightly after L-NAME administration, but the
changes did not reach statistical significance. The bottom
left panel of Fig. 1 shows that urine volume doubled after 60 min
of L-NAME administration (P < 0.05)
compared with the period before administration of L-NAME.
We conclude that inhibition of NO synthesis produces a significant
diuretic effect in mice.
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Effects of L-NAME on proximal tubule absorption of
fluid and HCO3.
We also investigated the effects of inhibition of NO synthesis on
HCO3
and Na+ transport by microperfusion
of proximal tubules in vivo. Data are summarized in Fig.
2 and Table
1. L-NAME, given by bolus iv
60 min before samples were collected and added to the luminal perfusion
solution (100 µM), significantly decreased both
Jv and JHCO3.
Jv decreased by 62%, from 1.57 to 0.60 nl · min
1 · mm
1, and
JHCO3 decreased by 49%, from 114.0 to 58.0 pmol · min
1 · mm
1,
respectively (P < 0.001). The perfusion rates,
perfused tubular length, and the HCO3
concentration
measured in the original perfusates were similar in the control and
experimental groups. These results indicate that inhibition of NO
synthesis decreases proximal tubule absorption of fluid and
HCO3
directly rather than by a secondary effect due
to changes of blood pressure and GFR.
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Proximal tubule HCO3 and fluid absorption in
nNOS-knockout mice.
Our data show that blocking NOS by L-NAME increases urine
volume and Na+ excretion and decreases proximal tubule
absorption of HCO3
and Na+. Because all
three NOS isozymes are inhibited by L-NAME, our results do
not indicate which NOS isozyme(s) is involved in proximal tubule
transport. Therefore, we examined the urine pH and
HCO3
concentration in nNOS, iNOS, and eNOS-knockout
mice. As shown in Fig. 3, urinary
HCO3
was significantly higher in the nNOS-knockout
animals compared with other groups of mice, although small increases of
urine pH and HCO3
were also observed in iNOS-knockout
mice and no differences were observed in eNOS-knockout mice. Because
nNOS participates more importantly in the control of
HCO3
absorption than the other isozymes, we studied
the proximal tubule transport of HCO3
and
Na+ in nNOS-knockout mice.
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Blood-gas and plasma electrolytes in nNOS-knockout mice.
Because proximal tubule JHCO3 and
Jv values are significantly lower and urinary
HCO3 excretion significantly higher in
nNOS
/
compared with nNOS+/+ mice, it is
important to know whether the blood pH and HCO3
concentration are affected by this lower
JHCO3. As shown in Table 3, the arterial blood
HCO3
concentration was reduced from 25.7 to 20.7 mM
(P < 0.05) and pH from 7.34 to 7.27 in
nNOS
/
mice (P < 0.05). This indicates
that animals lacking intact nNOS have a modest but significant
metabolic acidosis.
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DISCUSSION |
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Our previous data have shown that inhibition of NOS by
L-NAME increased urine volume and Na+ excretion
in rats; L-NAME decreased whereas NO donors enhanced fluid
and HCO3 absorption in the rat proximal tubule
(40). The present study shows that L-NAME
induces similar changes in tubule transport in mice. Second, we show
that a significant component of proximal tubule fluid and
HCO3
absorption is controlled by nNOS, whereas iNOS
may have little effect on HCO3
transport. Third, we
observed significant metabolic acidosis in nNOS-knockout mice,
supporting the view that this isoform of NOS participates in the
regulation of acid-base balance.
It has been suggested that NO is important in the chronic adaptation to
increased sodium intake (24, 32, 48) and that NO regulates
proximal tubule transport of Na+ (2, 9, 13,
30). However, the reported effects of NO on transport include an
increase (2, 9) or a decrease in proximal tubule transport
of Na+ and fluid (13, 30). These contrasting
NO effects may be due to differences in the renal tubule preparations
used (isolated tubules and cells vs. tubules perfused in vivo) or the
concentrations of inhibitors or NO donors employed. Indeed, in a
previous study we found that low concentrations of NO donors stimulate
whereas high concentrations inhibit fluid and HCO3
transport in the proximal tubule (40). The data in our
present study show that inhibition of NOS by the nonspecific inhibitor L-NAME significantly decreased fluid and
HCO3
absorption in the proximal tubule. These results
indicate that endogenous NO increases fluid and HCO3
transport but do not indicate which isozyme is involved in this regulation. For these reasons, use of genetically altered mice offers a
unique opportunity to study the role of NO in regulation of kidney
tubule transport and to distinguish the important isozyme(s).
In the absence of nNOS, Jv and
JHCO3 were significantly lower than in wild-type
control mice, indicating that a significant component of fluid and
HCO3 absorption is controlled by the action of nNOS.
These results parallel the effects of L-NAME, which
decreased Jv and JHCO3 in both rat and mouse proximal tubule and support our previous conclusion that endogenous NO enhances fluid and HCO3
transport
(40). Other isoforms of NOS, iNOS, and eNOS may play a
lesser role in the regulation of proximal tubule transport.
Arterial blood pH and HCO3 were significantly
decreased in nNOS-knockout mice, indicating a significant metabolic
acidosis. Acute inhibition of NOS by bolus iv of L-NAME had
only a transient effect on urine volume and did not significantly
affect blood pH and HCO3
. Although the
HCO3
absorption in the proximal tubule decreased
60%, the blood HCO3
decreased only 19% in
nNOS-knockout mice, similar to the data obtained from Na/H exchanger
(NHE3)-knockout mice (31, 46). This suggests a
compensatory increase in HCO3
absorption in the late
nephron, including upregulation of H+ secretion and K/H
exchange. This has also been observed in animals lacking the NHE3
isoform (31). Another possible compensatory mechanism may
be a reduction in GFR in nNOS-knockout mice due to activation of
tubuloglomerular feedback by the increased delivery of fluid and
Na+ to the macula densa. This in turn would be expected to
reduce the filtered load of HCO3
and thereby limit
the delivery of HCO3
from the proximal tubule, even
in the presence of a reduced capacity for HCO3
absorption. Additional free-flow micropuncture experiments are required
to investigate the mechanism of this compensation.
Blood pressure was lower in the nNOS-knockout mice, indicating nNOS and eNOS differ in the modulation of blood pressure; eNOS lowers, whereas nNOS raises blood pressure. This conclusion is also supported by the finding that eNOS-knockout animals have high blood pressure (16, 34) and that nNOS-selective inhibitors reduced the blood pressure in eNOS- knockout mice (19). The mechanism of low blood pressure in the nNOS-knockout mice is not clear. Possible explanations include the fact that extracellular volume is reduced by lower tubule absorption of Na+ in nNOS-knockout mice. Indeed, the hematocrit was slightly higher in the knockout mice (48.5 vs. 45.6%), suggesting that plasma volume might be lower in the knockout mice, but these changes did not reach statistical significance.
It is important to know the mechanism of lower
Jv and JHCO3 in the
absence of nNOS, especially because there is no direct evidence of nNOS
expression in the proximal tubule. One possibility is that under
physiological conditions, NO produced through the nNOS in Bowman's
capsule may go downstream to reach the proximal tubule and decrease
endogenous ANG II activity. In the absence of nNOS, endogenous ANG II
activity increased. It has been suggested that NO represents a
physiological antagonist of ANG II in both the glomerulus and tubule
(6, 9, 35). This view is supported by the observation that
ANG II blockers prevented the decrease in both single-nephron GFR and
proximal tubule absorption during inhibition of NOS (9)
and NO donors abolished the stimulation of fluid uptake by luminal ANG
II (11). The effects of ANG II on proximal tubule
HCO3 and Na+ transport are dose
dependent: low concentrations (10
12 to 10
11
M) stimulate, whereas high concentrations (10
8 to
10
5 M) inhibit Na+ and HCO3
transport (14, 41, 42). It is possible that in the mice lacking NO, the activity of ANG II increased, or the local ANG II
concentration increased, to reach a level high enough to produce inhibition of proximal tubule transport. Indeed the ANG II
concentration in proximal tubule fluid is in a range of
10
8 to 10
9 M, at the border between the
stimulatory and inhibitory level (29).
The second possibility is that there is an abnormality in renal nerve
development and the adrenergic nerve activity decreased in the absence
of nNOS (18). It has been reported that nNOS might play a
role in the development of renal catecholaminergic nerves
(23). In addition, it has been shown that nNOS expressed in the kidney is associated with nerve bundles (21, 22)
and cortical tubules in the rat kidney, especially the proximal tubule receive nerve endings (5, 10). Stimulation of renal
sympathetic nerves enhances proximal water and Na+
reabsorption (5); renal denervation induces a significant decrease in water and HCO3 absorption in the proximal
tubule (20), and stimulation of adrenergic receptors by
norepinephrine increases HCO3
and Na+
absorption in the proximal tubule (7, 8).
In summary, we have found that inhibition of NOS by L-NAME
decreases fluid and HCO3 absorption in the proximal
tubule of mouse kidney. A significant component of fluid and
HCO3
absorption is controlled by the effect of nNOS,
and defective absorption of fluid and HCO3
in the
proximal tubule in nNOS-knockout mice results in metabolic acidosis and
hypotension. The present study demonstrates that NO, in addition
to its role in the regulation of blood pressure and hemodynamics
(38), modulates fluid and HCO3
absorption
in the proximal tubule via changes in nNOS activity and also
participates in the maintenance of acid-base balance. Further study is
needed to investigate whether any clinical diseases with hypotension
and/or metabolic acidosis are caused by nNOS mutation.
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ACKNOWLEDGEMENTS |
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We thank Drs. R. Berliner and G. Giebisch for reviewing the manuscript and providing constructive comments and Leah Sanders for assistance in its preparation.
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FOOTNOTES |
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Portions of the study were previously published in abstract form (44). This work was supported by National Institutes of Health Grants DK-17433 and RO1-NS-29837.
Address for reprint requests and other correspondence: T. Wang, Dept. of Cellular and Molecular Physiology, Yale Univ. School of Medicine, 333 Cedar St., New Haven, CT 06520.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 4 February 2000; accepted in final form 23 May 2000.
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