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*
National Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health, Bethesda, Maryland
Department of Medicine, University of Michigan, Ann Arbor,
Michigan
Department of Pathology, UCLA-Harbor Medical Center, Torrance,
California.
Correspondence to Dr. Jurgen Schnermann, NIDDK, NIH, Building 10, Room 4 D51, 10 Center Drive MSC 1370, Bethesda, MD. Phone: 301-435-6580; Fax: 301-435-6587; E-mail: jurgens{at}intra.niddk.nih.gov
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies in rats in which pharmacologic inhibitors of NOS caused augmentation of TGF responses support such a possibility (3,4,5,6,7,8,9). Thus, constitutive release of NO seems to attenuate the vasoconstrictor response to increased MD NaCl and to reset TGF to higher flow rates. Conclusions concerning the physiologic role of NOS enzymes based on studies with pharmacologic inhibitors are limited by the selectivity and specificity of drug action, as well as by the need of the drug to reach its target. In the juxtaglomerular region, there is evidence for inducible NOS in the glomerular mesangium and for eNOS in the renovascular endothelium, in addition to nNOS in the MD (1). Thus, the role of nNOS in MD cells for the control of glomerular vascular tone cannot be established with certainty from experiments that use more or less unselective NOS inhibitors. The aim of the present study in nNOS knockout mice was to gain further insights into the role of MD nNOS in the control of glomerular vascular tone (10).
Our results show that nNOS deficiency did not affect the ability to autoregulate renal blood flow (RBF). Furthermore, TGF responses of stop-flow pressure (PSF) to saturating increases of loop of Henle flow rate were not augmented in nNOS-deficient mice. However, the acute augmentation of TGF responses caused by luminal application of the unselective NOS inhibitor nitro-L-arginine (NLA) in wild-type mice was not observed in nNOS knockout mice. Chronic nNOS deficiency causes a significant reduction in single-nephron GFR (SNGFR) that can be normalized by abolishment of perfusion of the MD segment. We conclude that MD-derived NO tonically attenuates the GFR-reducing influence of the TGF-mediating vasoconstrictor.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals were maintained on a standard rodent chow and tap water. Male and female mice in the weight range between 21 and 45 g were anesthetized with 100 mg/kg inactin intraperitoneally and 100 mg/kg ketamine intramuscularly. Body temperature was maintained at 38°C by placing the animals on an operating table with a servo-controlled heating plate. The trachea was cannulated, and a stream of 100% oxygen was blown toward the tracheal tube throughout the experiment. The femoral artery was cannulated with hand-drawn polyethylene tubing for measurement of arterial BP and blood withdrawal, and the jugular vein was cannulated for an intravenous maintenance infusion of 2.25 g% bovine serum albumin in saline at a rate of 0.5 ml/h. The left kidney was approached from a flank incision, freed of adherent fat and connective tissue, and placed in a lucite cup adapted for the size of the mouse kidney. The kidney was covered with mineral oil.
Micropuncture Studies
Measurements of PSF during loop of Henle perfusion was done by
identifying a late proximal tubule segment from the staining pattern after
microperfusion of a randomly selected proximal segment with the
FD&C-stained perfusate. The tubule was blocked with wax, the pump was
inserted into the last superficial proximal segment, and the pressure pipette
was inserted into an early proximal segment recognizable from the widening of
the tubular lumen. When PSF had stabilized, the loop of Henle
perfusion rate was altered between 45 and 0 nl/min in a random manner. Flow
rates tested were 0, 5, 7.5, 10, 15, 25, and 45 nl/min. The perfusion fluid
contained 136 mM/L NaCl, 4 mM/L NaHCO3, 4 mM/L KCl, 2 mM/L
CaCl2, 7.5 mM/L urea, and 100 mg/100 ml FD&C green (Keystone).
In experiments in which the effect of NLA was assessed, the agent was added to
the perfusate at a concentration of 10-3 or 10-2 M.
After an initial determination of the PSF response during Ringer
perfusion, tubules were perfused with NLA containing solution for 15 min.
Subsequently, the pipette that contained Ringer was reintroduced and the
PSF response to Ringer solution was tested again.
For determination of nephron filtration and absorption rates, mice were infused with 125I iothalamate (Glofil; Questcor Pharmaceuticals, Hayward, CA) at approximately 40 µCi/h. The first blood samples were obtained after 45 min of equilibration. Free-flow micropuncture was performed according to techniques used previously in rats (13). Briefly, end-proximal and distal segments were identified by injection of a bolus of artificial tubular fluid stained with FD&C green from a 3- to 4-µm tip pipette connected to a pressure manometer. This pipette remained in place during the collections, to permit control of intratubular pressure. All proximal collections were done in the last surface segment, whereas distal collections were restricted to early sites corresponding to the first of two surface segments. Distal and proximal fluid collections (collection times 3.5 to 5 min) were done in a paired manner in two to three nephrons per kidney with the use of oil-filled pipettes. Fluid volume was determined from column length in a constant bore capillary. After volume determinations, a 1-nl sample was removed for determination of Cl concentration by use of electrometric titration (14). The remainder of the sample was transferred into a counting vial, and radioactivity was determined in a gamma counter. Blood samples were collected in heparinized 5-µl microcaps at the beginning of micropuncture, after 45 to 60 min, and after 110 to 120 min. 125I iothalamate radioactivities were measured in duplicate by use of 0.5-µl samples of plasma and urine. Experiments did not extend beyond 2 h.
Renal Blood Flow
For determination of RBF, the left renal artery was approached from an
abdominal midline incision. After careful dissection of the left renal artery,
a 0.5-mm, V-type ultrasonic flow probe (Transonic Systems, Ithaca, NY) was
placed around the vessel and held in place with a micromanipulator. For
assessment of steady-state autoregulation, an adjustable clamp was placed
around the aorta proximal to the origin of the renal arteries. Mean arterial
BP in these mice was elevated by tying off the superior mesenteric and celiac
arteries as well as the aorta below the renal arteries around the femoral
artery catheter, which in these studies had been advanced into the abdominal
aorta.
Immunocytochemistry
Kidneys were bisected and immersed in Zamboni's fixative overnight,
followed by immersion in graded sucrose solutions for cryoprotection (10%
sucrose for 2 to 4 h and 20% sucrose overnight at 4°C, both solutions in
0.1 M phosphate buffer [pH 7.4]). For immunocytochemistry, the
immunoperoxidase method that uses avidinbiotinylated horseradish peroxidase
complex (ABC; Vector Laboratories, Burlingame, CA) was applied to frozen
sections (10 µm thickness). Sections were incubated at room temperature
overnight with antisera against nNOS (kindly provided by H. H. W. Schmidt, R.
Buckheim Inst. Pharm., Giessen, Germany, and J. Pollock, Medical College of
Georgia, Augusta, GA) at a dilution of 1:500 in phosphate-buffered saline that
contained 0.3% Triton X-100 and 10% goat serum. The second incubation was
carried out with biotinylated goat anti-rabbit IgG for 2 h at room
temperature. Endogenous peroxidases were inactivated with 2.5% hydrogen
peroxide in methanol. Sections were subsequently incubated in an avidin and
biotinylated horseradish peroxidase mixture for 2 h, in a solution containing
0.05% diaminobenzidine in Tris buffer for 20 min and in 0.05% diaminobenzidine
and 0.005% hydrogen peroxidase in Tris buffer for 10 min. Control sections
were incubated with (1) nonimmune rabbit serum diluted 1:500 in
phosphate-buffered saline and (2) with nonimmune goat serum diluted
1:30 in phosphate-buffered saline. Sections were mounted in Protexx (Lerner
Laboratory, New Haven, CT) and examined and photographed with a Zeiss Axiophot
photomicroscope (Carl Zeiss Inc., Thornwood, NY).
Statistical Analysis
Statistical comparisons between results from wild-type and knockout mice
were done by unpaired or paired t test. P < 0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood Flow Autoregulation
RBF in nNOS +/+ mice after ligation of the superior mesenteric and celiac
arteries averaged 1.7 ± 0.26 ml/min at a pressure of 117 ± 1.2
mmHg (n = 6). In nNOS -/- animals, mean RBF was 1.4 ± 0.1
ml/min (P = 0.12 compared with wild type; n = 6) at a
pressure of 118 ± 1.5 mmHg. RBF autoregulation was determined by
assessment of the response of RBF to stepwise reductions in renal perfusion
pressure. Autoregulation was found to be demonstrable to a pressure level of
approximately 85 mmHg in both wild-type and nNOS -/- mice
(Figure 2).
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Tubuloglomerular Feedback Responses of PSF
PSF responses in wild-type and nNOS -/- mice at zero loop flow
averaged 40.7 ± 2.3 mmHg in wild-type (5 mice, 13 tubules) and 40.6
± 1.6 mmHg in nNOS -/- mice (5 mice, 18 tubules). In response to
maximum flow stimulation (45 nl/min), PSF fell to 32.2 ± 2.1
and 31.6 ± 1.9 mmHg in wild-type and nNOS -/- mice, respectively. Thus,
maximum PSF responses of 8.5 ± 1 and 9.1 ± 1 mmHg in
wild-type and nNOS -/- mice were not significantly different. In addition, as
shown in Figure 3,
PSF responses were indistinguishable between genotypes over the
entire flow range. Arterial BP in this experimental series was 96 ± 4
mmHg in wild-type and 100 ± 2 mmHg in nNOS -/- mice.
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Effect of Luminal NLA in Wild-Type and nNOS -/- Mice
In wild-type mice, an increase in loop perfusion rate from 0 to 30 nl/min
caused a reduction in PSF from 39.1 ± 1 to 32 ± 1
mmHg (5 mice, 16 tubules). After 15 min of perfusion with NLA (10-3
M or 10-2 M; results with the two concentrations were not different
and therefore were lumped together), PSF fell from 39.3 ± 1
to 26.7 ± 1.9 mmHg. Although the difference in TGF responses (7.1
± 1 versus 13 ± 2 mmHg) was significant (P
< 0.001), single tubule responses to NLA were highly variable, with some
nephrons showing substantially exaggerated responses (see example in
Figure 4) and others being
practically unaffected by NLA (Figure
5). In nNOS -/- animals, PSF fell from 36.5 ±
1.8 to 29.8 ± 2 mmHg before NLA and from 36.5 ± 1.7 to 28.7
± 1.9 mmHg after NLA (5 mice, 13 tubules). Maximum TGF responses of 7
± 1 before and 8 ± 1 mmHg after NLA were not significantly
different. Mean arterial BP was 97 ± 4 mmHg in wild-type and 95
± 2 mmHg in nNOS -/- mice.
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Free-Flow Micropuncture Data
Functional and morphologic data obtained in this series of experiments are
summarized in Table 1. Body
weight was significantly lower in the nNOS -/- mice, even though mice were age
matched. All other variables were statistically indistinguishable between the
nNOS genotypes.
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Paired measurements of SNGFR in distal and proximal segments in the two groups of mice are shown in Figure 6, and mean values are shown in Table 2. The main observation is that SNGFR measured in distal segments was significantly lower in nNOS -/- than in nNOS +/+ mice, whereas SNGFR measured in proximal segments was not different between genotypes. The proximal-distal SNGFR difference was 0.8 ± 0.4 nl/min in nNOS +/+ but 3.1 ± 0.4 in nNOS -/- mice (P < 0.0001).
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Proximal fractional fluid absorption was significantly higher in nNOS -/- mice than nNOS +/+ mice (P = 0.002). Cl concentration at the end of the proximal convolution was higher than in plasma and was the same in wild-type and knockout mice. Fractional Cl absorption along the proximal tubule was significantly higher in nNOS -/- mice (P = 0.0006). Tubular fluid flow rate in the distal tubule was lower in nNOS -/- mice as a reflection of the lower SNGFR, but fractional fluid absorption to the distal puncture site was not different between genotypes, which indicates an unaltered match between delivery and absorption rates. Because distal Cl concentrations were the same, fractional Cl absorption rates to the distal tubules also were the same between nNOS +/+ and -/- mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is an obvious requirement for the usefulness of the available nNOS
knockout strain that MD cells of nNOS—/— mice do in fact lack the
enzyme. Clarification of this question gained some urgency after the
demonstration of a residual, enzymatically active nNOS in the brain of
nNOS—/— mice by Brenman et al.
(15). This nNOSß protein
is translated from a shorter nNOS mRNA splice variant that lacks the second
exon, the part of the nNOS gene targeted in the gene-disruption approach
(10). However, as shown here
and in previous studies, polyclonal antibodies against nNOS consistently fail
to detect nNOS protein in MD cells of nNOS—/— mice
(10). Furthermore, a specific
antibody against the portion of nNOS encoded by exon 2 stained MD cells of
wild-type mice but not of knockout animals
(16). Thus, all currently
available evidence indicates that MD cells normally express the longer
nNOS
and that MD cells of nNOS—/— mice therefore are devoid
of nNOS activity (17).
There was a tendency for both RBF and GFR to be lower in nNOS—/— than in wild-type mice, but the difference in RBF and GFR did not reach statistical significance. Previous studies showed that acute administration of the nNOS-specific inhibitors 7-nitroindazole or S-methyl-L-thiocitrulline causes reductions in GFR, RBF, or both (18, 19). Furthermore, both afferent and efferent vasoconstriction has been observed in response to the nNOS inhibitor S-methyl-L-thiocitrulline (20). We believe that our failure to demonstrate statistically significant reductions in GFR and RBF is due to the nonpaired nature of our comparisons and a relatively small number of observations. Chronically nNOS-deficient mice retain the ability to autoregulate RBF, which supports the conclusion from earlier studies that autoregulation does not critically depend on NO expression in MD cells (21, 22).
In contrast to previous rat studies, TGF responses were indistinguishable between nNOS—/— and nNOS+—+ mice when changes in PSF were used as an index of TGF. The observation that luminal NLA enhanced TGF responses in nNOS+/+ mice but not in nNOS—/— mice, indicates that nNOS is in fact the NOS that causes TGF attenuation. It is possible that a difference in the chronicity of nNOS inhibition is causal in the different effects on maximal TGF responses. A lifelong nNOS deficiency may be associated with adaptations that compensate for the TGF-enhancing effect of a loss of NO release from the MD. There is some evidence that renal renin expression is reduced in nNOS—/— mice, even though this result is not unequivocal (23, 24). Nevertheless, the TGF-blunting effect of a reduction in angiotensin II may compensate for the TGF-enhancing effect of nNOS deficiency.
Determining PSF responses to loop of Henle microperfusion may not fully describe TGF characteristics, because PSF measurements as surrogate for glomerular capillary pressure responses have been found not always to mirror the responses of SNGFR (25, 26). Furthermore, changes in loop flow between 0 and 5 nl/min, the subnormal flow range in the mouse, are difficult to establish reliably by microperfusion; therefore, small differences in PSF responses may be difficult to ascertain. For assessment of the influence of ambient low flows past the MD on SNGFR in wild-type and nNOS knockout mice independent of microperfusion, SNGFR was determined by collection of tubular fluid in early distal and late proximal tubules in a paired manner. Although distal SNGFR measurements assess steady-state GFR, proximal fluid collections are made during acute reductions of the TGF signal to minimal levels. The proximal-distal SNGFR difference therefore is a measure of the ambient GFR-restraining effect of the MD. Consistent with earlier observations from our laboratory, the proximal-distal SNGFR difference in wild-type mice was small (27, 28). In contrast, nNOS—/— animals had a markedly increased proximal-distal SNGFR difference. This finding indicates that the ambient flow at the MD exerts a greater constrictor effect in the absence of nNOS, a conclusion in agreement with the notion that NO derived from the MD attenuates TGF responses. Thus, MD-derived NO may permit an increase in distal fluid and electrolyte load consistent with its proposed role in TGF resetting (8). An increase in the proximal-distal SNGFR difference during NOS inhibition with NLA was found previously in rats on a high-NaCl diet (29). In accordance, an augmentation in TGF-mediated reductions of SNGFR in response to a change in loop flow from zero to approximately normal was observed previously in the rat (9). Our observation that SNGFR determined by proximal collections, i.e., in the absence of MD perfusion, showed no difference between wild-type and nNOS—/— mice is consistent with observations in the perfused juxtamedullary preparation, where a specific nNOS inhibitor had no effect on arteriolar diameter when MD flow was interrupted (20).
Because distal C1 concentrations were identical between nNOS+/+ and nNOS—/— mice, the increase in the SNGFR response cannot be explained by a primary inhibition in tubular transport along the thick ascending limb and increased delivery to the MD. We cannot exclude the possibility that NO generated by MD cells normally inhibits MD NaCl transport in an autocrine manner, so that transport may be disinhibited in the nNOS—/— mice and cause TGF augmentation. An increase in MD cyclic guanosine monophosphate was invoked recently as a cause for NO-mediated TGF attenuation, and it is possible that cyclic guanosine monophosphate exerts its effect through inhibition of MD transport (30). Whatever the precise mechanism, it is likely that nNOS deficiency in the MD is primarily and directly responsible for the enhanced effect of ambient flow rate changes on SNGFR.
The difference in TGF responses of PSF and of SNGFR to subnormal flow rate changes in the nNOS knockout mice may be analogous to earlier evidence in rats that glomerular capillary pressure does not always rise with acute reductions in distal tubular NaCl delivery (26). The increase in SNGFR in response to a reduction in ambient luminal NaCl at the MD is the result of both afferent and efferent arteriolar vasodilation, a response that increases plasma flow, and thus SNGFR, without a significant change in glomerular capillary pressure (25, 26). MD-dependent changes in glomerular capillary pressure are expected to contribute predominantly to the fall in SNGFR, predicted to occur when the ambient distal tubular NaCl delivery is increased above normal. Thus, differences in proximal-distal SNGFR are not incompatible with unaltered MD-dependent changes in glomerular capillary pressure.
It is unexpected that fractional absorption of fluid and chloride along the proximal convoluted tubule was increased in nNOS—/— mice. Because proximally determined SNGFR was nearly identical, the absolute rates of fluid and chloride absorption also tended to be higher in nNOS—/— mice. Previous reports of the effect of NO on proximal fluid absorption have been controversial, with NO causing either inhibition or stimulation of transport (1). In addition, most earlier studies are not directly comparable to our observations, because widely varying preparations and different methods to alter NO availability have been used. However, in a recent study by Wang et al. (31), fluid and HCO3 absorption rates were found to be 60 and 49% lower in microperfused proximal tubules of nNOS—/— compared with wild-type mice. It is possible that the use of an artificial perfusion fluid leads to the omission of some factor in tubular fluid that maintains fluid absorption in the nNOS—/— mice in vivo. Because tubules were perfused with slightly elevated flow rates compared with free flow, another speculation may be that fluid absorption at ambient in vivo flow rates are comparable between genotypes but that the mechanism of transport adaptation to elevated flows is defective in the knockout mice. Fluid and C1 absorption also was comparable along the loop of Henle. Inhibition of C1 absorption by NO was observed previously, but the source of this NO was determined to be eNOS, not nNOS (32, 33).
In summary, the major contribution of this study is the demonstration that the transformation of an increase in loop of Henle flow rate in the range of ambient flows into a GFR suppression is attenuated by NO derived from MD nNOS. Thus, independent of specificity and distribution of NOS inhibitors, these results provide evidence that NO derived from nNOS is an important modulator of TGF responses.
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-) and nNOS
knockout mice (nNOS -/-, --[UNK]--).
