1 Department of Medicine, 2 Center for In Vivo Microscopy, Duke University, and Veterans Affairs Medical Centers, Durham 27710; 4 Departments of Pharmacology and Physiology, Bowman Gray School of Medicine, Winston-Salem 27257; 5 Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27599; and 3 Department of Pharmacology, Wright State University, Dayton, Ohio 45401
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ABSTRACT |
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Mice lacking AT1A
receptors for ANG II have a defect in urinary concentration manifested
by an inability to increase urinary osmolality to levels seen in
controls after thirsting. This defect results in extreme serum
hypertonicity during water deprivation. In the basal state, plasma
vasopressin levels are similar in wild-type controls and
Agtr1a /
mice. Plasma
vasopressin levels increase normally in the
AT1A receptor-deficient mice after
24 h of water deprivation, suggesting that the defect in urine
concentration is intrinsic to the kidney. Using magnetic resonance
microscopy, we find that the absence of
AT1A receptors is associated with a modest reduction in the distance from the kidney surface to the tip
of the papilla. However, this structural abnormality seems to play
little role in the urinary concentrating defect in
Agtr1a
/
mice since the
impairment is largely reproduced in wild-type mice by treatment with an
AT1-receptor antagonist. These
studies demonstrate a critical role for the
AT1A receptor in maintaining inner
medullary structures in the kidney and in regulating renal water excretion.
gene targeting; urinary concentration; magnetic resonance microscopy; papilla; vasopressin
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INTRODUCTION |
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THE RENIN-ANGIOTENSIN system (RAS) regulates body fluid balance. Although the effects of this system on blood pressure and renal sodium reabsorption have been most thoroughly studied, ANG II also modulates water homeostasis. In the central nervous system, ANG II stimulates the synthesis and release of vasopressin and acts as a potent dipsogen (11, 27, 28). Along with these actions in the brain, ANG II may modulate urinary concentrating mechanisms in the kidney through its effects on hemodynamics and perhaps through direct effects on renal epithelia. ANG II causes vasoconstriction of afferent and efferent arterioles and may modulate Starling forces in the peritubular capillaries of the proximal nephron to favor solute and water reabsorption (6). ANG II-mediated vasoconstriction also decreases medullary blood flow and thus may affect osmolar gradients (3, 7, 10, 19). AT1 receptors are expressed in proximal tubular cells where they act to stimulate proximal sodium reabsorption directly and therefore may also affect water handling by reducing solute delivery to the distal nephron (21). Finally, expression of AT1 receptors in thick ascending limb and collecting duct epithelia and medullary interstitial cells suggests that these receptors might have more direct effects on distal water handling (20, 38). In both the brain and the kidney, pharmacological studies suggest that the effects of ANG II on water homeostasis are mediated by type 1 (AT1) angiotensin receptors (33).
The physiological effects of the RAS to stimulate thirst and vasopressin secretion are consistent with its role in protecting the extracellular fluid volume. In addition to these direct physiological effects, recent studies using gene targeting suggest that ANG II may also play a role in the development or maintenance of structures within the kidney that determine urinary concentration. For example, Niimura et al. (22) found that angiotensinogen-deficient mice develop marked atrophy of the renal papilla. Esther and associates found similar abnormalities in angiotensin-converting enzyme (ACE)-deficient mice, and these anatomic alterations are associated with high urine volumes and reduced urine osmolalities (9, 24). The similarity of these defects in angiotensinogen- and ACE-deficient mice suggests a key role for ANG II in maintaining the normal anatomic configuration of the inner medulla. Although disruption of individual angiotensin receptor genes, including the AT1A receptor gene locus, does not reproduce these obvious structural abnormalities, severe atrophy of the inner medulla has been observed in mice with combined deficiency of AT1A and AT1B receptors (25, 34). It has been suggested that this abnormal inner medullary structure may result from the absence of AT1 receptor actions to promote ureteral peristalsis (18). The complete absence of AT1 signaling is essential for the pathogenesis of this abnormality. However, the absence of either AT1A or AT1B receptors alone is not sufficient to produce this severe defect.
In our preliminary studies, we found that urine volumes were
significantly increased in Agtr1a
/
mice, which lack
AT1A receptors, whereas their
kidney morphology appeared essentially normal. Thus we used
Agtr1a
/
mice to define
the contribution of the AT1A receptor to the regulation of urinary concentration. To develop a more
comprehensive view of kidney structure and to assess the potential
contribution of renal structural changes to abnormal water metabolism
in Agtr1a
/
mice, we
examined their kidneys using magnetic resonance microscopy. We find
that water homeostasis is abnormal in
Agtr1a
/
mice primarily
due to functional changes within the kidney.
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METHODS |
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Animals. Mice lacking
AT1A receptors for ANG II were
generated by homologous recombination in embryonic stem cells as
previously described (12). Animals were bred and maintained in the
animal facility of the Durham Veterans Affairs Medical Center under
National Institutes of Health guidelines.
Agtr1a genotypes, designated "+"
for the wild-type allele and "" for the targeted allele, were determined by Southern blot analysis of DNA isolated from tail
biopsies (12). Mice were generated from crosses of
(129×C57BL/6)F1 Agtr1a +/
parents. The
F2 generation
Agtr1a +/+ and
/
animals derived from these crosses were used in these experiments. We studied
both male and female mice that were 2-4 mo old.
Measurement of serum and urine
osmolality. The effect of the
Agtr1a mutation on the regulation of
serum and urine osmolalities was examined in mice housed in standard
cages allowed free access to 0.4% NaCl chow. Serum and urine were
collected first from Agtr1a +/+
(n = 12) and
Agtr1a /
(n = 10) mice that had free access to
drinking water and then in separate groups of
Agtr1a +/+
(n = 7) and
Agtr1a
/
(n = 5) mice that had been deprived of
water for 48 h. After the collection of a urine sample by bladder
massage, the animals were anesthetized with isoflurane, and a blood
sample was obtained by cardiac puncture without heparin. All urine and serum osmolalities were measured immediately using a vapor pressure osmometer (Wescor Instruments).
Effects of altered water intake in Agtr1a
+/+ and Agtr1a /
mice. To
examine the effect of the Agtr1a
mutation on drinking behavior, urinary flow rate, and urine
concentration, Agtr1a +/+ (n = 15) and
Agtr1a
/
(n = 13) mice 2-4 mo of age were
housed in specially constructed metabolic cages. During an initial 24-h period, water intake and urine volumes were measured while the animals
had free access to water. Water bottles were then removed, and urine
output and osmolality were measured during 48 h of water deprivation.
Drinking and urine flow rates are expressed as milliliters per 24 hours
per 20 grams of body weight. Osmolality of urine was measured in
samples obtained by bladder massage just before the onset of water
deprivation and at 24-h intervals thereafter. All animals were allowed
free access to 0.4% NaCl chow during the entire experiment.
A separate group of Agtr1a +/+
(n = 6) and
Agtr1a /
(n = 6) mice received an
acute water load equivalent to 4% of their body weight, administered
by gavage. Urine osmolalities and body weights were measured in this
group just before the gavage and hourly thereafter until minimum urine
osmolality was achieved. Changes in body weight were used to monitor
delivery and excretion of the water load. Additional water and food
were withheld after administration of the water load and until the
completion of the experiment.
Measurement of plasma vasopressin. To
determine whether the Agtr1a null
mutation affects vasopressin levels, plasma was collected from separate
groups of adult male Agtr1a +/+ and
/
mice under the following two conditions:
1) with free access to drinking water (n = 7 for +/+,
n = 5 for
/
) and
2) after 24 h of water deprivation
(n = 7 for +/+,
n = 6 for
/
). Blood was
obtained by decapitation without anesthesia and collected into tubes
containing EDTA. Plasma samples were assayed simultaneously for
vasopressin by RIA according to the manufacturers' instructions
(Peninsula Laboratories).
Administration of desmopressin. We
examined the effect of desmopressin (dDAVP; Rhone-Poulenc Rorer,
Collegeville, PA) on urine osmolality in
Agtr1a +/+
(n = 4) and
Agtr1a /
(n = 4) mice. dDAVP is a selective
V2-receptor agonist and was selected for use in these studies because
it has potent antidiuretic effects with only modest vascular actions.
Before the experiments, animals were allowed free access to drinking
water and 0.4% NaCl chow. After the collection of a baseline urine
sample by bladder massage, mice were injected with 1.0 µg/kg dDAVP
subcutaneously, and water bottles were removed. Urine samples were
collected 4 h after injections, and urine omolalities were measured immediately.
Role of abnormal water drinking in the urinary
concentrating defect in Agtr1a /
mice. In
our initial experiments, we found that the daily water intakes were
significantly greater in Agtr1a
/
compared with Agtr1a
+/+ mice. To further examine the contribution of the level of water
intake to the urinary concentrating defect observed in
Agtr1a
/
mice, we
performed paired drinking experiments. Over a 3-day adaptation period,
mice (n = 6 for each genotype) were
housed in standard cages and allowed free access to drinking water and
0.4% NaCl chow. Baseline body weights, water intake, and urine
osmolalities were measured, and each
Agtr1a
/
mouse was
paired with an Agtr1a +/+ mouse based
on similar body weights. Over the next 5 days, the water
intake in each Agtr1a
/
mouse was restricted to the volume of water ingested by its paired +/+ control during the preceding 24 h. Body weights, water intake, and
urine osmolality were measured throughout the experiment.
Magnetic resonance microscopy of mouse
kidneys. The unique strengths of magnetic resonance
microscopy in defining organ structure have been demonstrated by
previous work (4, 13, 31). Thus to gain a more complete visualization
of the structure of the kidney, we performed magnetic resonance
microscopy of kidneys in groups of male
Agtr1a /
(n = 4) and
Agtr1a +/+
(n = 4) mice between 2 and 3 mo of
age. After anesthesia with isoflurane, the abdomen was opened, and the
left renal vein was immediately ligated to prevent blood from leaving
the organ so that it would act as a natural contrast agent. The excised
kidney was then placed in a cylindrical 10-mm-diameter container and
was immersed in Fomblin (perfluoro polyether) to limit
susceptibility variation at the surface of the tissues.
Magnetic resonance microscopy was performed using a tunable custom-designed 10-mm solenoid radio frequency coil. Three-dimensional magnetic resonance images of kidney specimens were acquired at 9.4 tesla on a Bruker CSI System (Fremont, CA) equipped with actively shielded gradients. A spin-echo pulse sequence was used, with the following parameters: time of repetition = 500 ms, echo time = 10 ms, NEX (no. of excitations) 2. Spatial encoding was accomplished using a three-dimensional Fourier transform encoding, which allowed the simultaneous imaging of 128 contiguous planes, each 51-µm thick, through the kidney specimen. The field of view was 13 mn and was reconstructed on a 256 × 256 matrix, leading to a voxel size of 51 × 51 × 51 µm. Images were displayed and analyzed on a Silicon Graphics workstation (Reality Engine2, SGI, Mountain View, CA) using VoxelView (Vital Images, Fairfield, IA), a commercial software package developed for interactive imaging. A plane crossing through the longest axis of the inner medulla in both coronal and axial planes was used for distance and area measurements. Using clear changes in signal intensity and image pattern, distinct kidney zones were differentiated in the coronal plane as follows: cortex and outer stripe were grouped together and distinguished from the inner stripe by the appearance of radial stripes representing vascular bundles (5); the border between the innermost zone of the inner stripe and the inner medulla could not be reproducibly distinguished in these unperfused kidneys, and these zones were therefore measured as one larger combined zone (inner stripe + inner medulla). These combined kidney zones were outlined, and their areas were measured using Voxel View. The area in pixels squared was multiplied by the pixel size (51 µm) and was used for statistical analysis. The linear distance from the kidney surface to the tip of the papilla was measured in each kidney.
Effects of pharmacologic AT1 receptor
blockade.
To determine whether the defects in urine concentration seen in
Agtr1a /
mice were due
to structural/developmental changes or the functional absence of
AT1A receptors in adult mice, we examined the urine concentrating capacity of adult (2-3 mo of age)
male Agtr1a +/+
(n = 18) and
/
(n = 6) mice before and after
treatment with losartan for 5 days. All mice were housed in standard
cages and were allowed free access to 0.4% NaCl chow throughout the
experiment. On day 1, water bottles
were removed, and all mice were given a subcutaneous injection of 0.9%
saline (vehicle) in a volume equivalent to 4 µl/g body wt 4 h later. This injection was repeated 23 h after water deprivation was begun. Urine was obtained by bladder massage 24 h after water deprivation, and
urine osmolality was immediately measured as described above. Water
bottles were then returned, and, after 4 h of reequilibration time,
mice began treatment with 30 mg · kg
1 · day
1
losartan (Merck, Piscataway, NJ) in drinking water, which lasted for 4 days. At this 4-day point, mice were again water deprived and
subsequently received subcutaneous injections of losartan (30 mg/kg) in
4 µl/g body wt saline 4 and 23 h after the initiation of water
deprivation. Urine osmolality was measured again after 24 h of
thirsting. Using a separate group of wild-type mice, we determined that
this losartan treatment protocol was sufficient to essentially block
the pressor response to infused ANG II at a dose of 10 µg/kg (data
not shown).
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RESULTS |
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The absence of AT1A receptors alters
urine and serum osmolality.
To examine the role of the AT1A
receptor for ANG II in water homeostasis, we first measured water
intake and urine flow rates in Agtr1a
/
and Agtr1a +/+ mice.
Agtr1a
/
mice with free
access to water drank significantly more than wild-type controls (4.3 ± 0.5 vs. 3.1 ± 0.2 ml · day
1 · 20 g
1;
P = 0.01). Urine flow rates were also
higher in Agtr1a
/
mice than in controls (2.1 ± 0.3 vs. 1.1 ± 0.1 ml · day
1 · 20 g
1;
P = 0.004). The increased urine flow
in Agtr1a
/
mice is
associated with a reduced urine osmolality compared with wild-type mice
(1,168 ± 168 vs. 1,766 ± 109 mosmol/kgH2O;
P = 0.007). When they are provided
free access to water, Agtr1a
/
mice have a lower mean serum osmolality compared with
Agtr1a +/+ controls (311 ± 2 vs. 318 ± 1 mosmol/kgH2O;
P = 0.01).
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Pharmacological blockade of AT1 receptors
produces a defect in urine concentration.
We estimated the relative importance of structural versus functional
effects of the absence of AT1A
receptor signaling on urinary concentrating mechanisms by examining the
effects of pharmacological blockade of
AT1 receptors with losartan in
Agtr1a +/+ and /
mice.
As shown in Table 2, urine osmolalities of
water-deprived Agtr1a
/
mice were significantly lower than those of
Agtr1a +/+ mice during vehicle
treatment (2,895 ± 184 vs. 3,673 ± 129 mosmol/kgH2O;
P < 0.005). Treatment with losartan
did not significantly alter urinary osmolality in thirsted
Agtr1a
/
mice. In
contrast, the AT1 receptor blocker
significantly reduced urine osmolality achieved after 24 h of
water deprivation in the wild-type animals (2,884 ± 147 mosmol/kgH2O;
P < 0.0001 vs. vehicle treatment). After losartan treatment, thirsted urine osmolalities were similar in
Agtr1a +/+ and
/
mice.
This indicates that a significant component of the urinary
concentrating defect that is observed in the
Agtr1a
/
mice is due to
functional effects caused by the absence of
AT1A receptor signaling.
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DISCUSSION |
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Among its many physiological effects, the RAS modulates water
homeostasis. This is accomplished through actions in the central nervous system and in the kidney. Our studies using
Agtr1a /
mice suggest a
key role for the AT1A receptor in
the regulation of water balance by the RAS. Water homeostasis is
abnormal in these animals and is most strikingly demonstrated by the
extreme hypertonicity that develops when
Agtr1a
/
mice are
deprived of water. Our studies indicate an essential role for the
AT1A receptor in maintaining water balance.
There is substantial evidence that links the functions of
AT1 receptors in the central
nervous system to the control of vasopressin secretion. For example,
AT1 receptors are present in
regions of the hypothalamus that synthesize vasopressin (35). In
addition, ANG II activates vasopressin-producing neurons (16), and
central administration of
AT1-receptor antagonists alters
the release of vasopressin induced by osmotic stimuli (28). Although
both AT1A and
AT1B receptors are expressed in
the central nervous system, their relative effects on vasopressin
secretion cannot be distinguished pharmacologically and therefore have
not been defined previously. Our studies demonstrate that plasma
vasopressin levels increase appropriately in
Agtr1a /
mice after 24 h
of thirsting and that a failure to augment vasopressin levels does not
explain the urinary concentrating defect seen in these animals.
Although these values for plasma vasopressin levels are somewhat higher
than those of other species such as rats and dogs, our values are
within the range of those reported previously by other investigators in
mice (32, 39). The preservation of this response in the absence of
AT1A receptors suggests that
AT1B receptors may mediate the interactions between the RAS and vasopressin release. Alternatively, the role of AT1 receptors in
regulating vasopressin responses in vivo may have been overestimated.
To examine the possibility that the absence of
AT1A receptors might affect renal
responses to vasopressin in collecting duct epithelium, we administered
a V2 receptor vasopressin analog to Agtr1a +/+ and
Agtr1a /
mice. After
dDAVP administration, we found that
Agtr1a
/
mice rapidly
and significantly increase their urine osmolality. Within both groups
of mice, the maximal osmolality achieved after this pharmacological
dose of dDAVP is similar to that observed after 24 h of water
deprivation. However, the maximal urine osmolality achieved by
Agtr1a
/
mice after dDAVP remained substantially less than that of controls. Thus the
absence of AT1A receptors does not
eliminate the actions of vasopressin to augment water permeability in
the distal nephron at the collecting duct level. Instead, the defect
appears to be related to the generation of a maximal osmolar gradient.
One potential explanation for a reduced capacity to generate maximally
concentrated urine would be a disruption of the medullary gradient due
to high urine flows caused by increased water intake. Such a
circumstance has been described in humans drinking copious amounts of
water and in water-loaded rats (8, 15). To test this possibility, we
restricted the water intake of Agtr1a
/
mice to the level of wild-type controls with similar
body weights. Over a period of 5 days, this regimen had no effect on
urine volume or osmolality, suggesting that medullary washout,
secondary to polydipsia, does not play a significant role in impairing
urinary concentrating ability in these animals.
The consequences of AT1A receptor
deficiency on renal hemodynamics might also contribute to abnormal
urinary concentration. For example, acute treatment of animals with an
ACE inhibitor increases blood flow in the renal inner medulla (3), and
an inverse relationship between papillary blood flow and inner
medullary solute accumulation has been reported (19). Similarly, acute AT1 receptor blockade with
losartan also increases papillary blood flow and urine flow (2, 23).
Inner medullary blood flow might be similarly dysregulated in
Agtr1a /
mice, limiting
the accumulation of osmotically active solute in the medullary
interstitium. However, chronic ACE inhibition in rats causes a
consistent increase in papillary plasma flow, but this does not impair
their ability to concentrate urine in response to thirsting (7).
Interruption of the direct epithelial actions of ANG II could
potentially explain the defective urine concentration of Agtrla /
mice. Proximal tubular AT1 receptors regulate
solute and fluid reabsorption at this site and thus could also affect
urine concentration by altering distal delivery of
solutes (21). AT1
receptors are also expressed in thick ascending limb, collecting duct,
and in medullary interstitial cells (20, 38). Because
AT1 receptors in these more distal
sites also seem to modulate sodium and bicarbonate flux (29, 36, 37),
interruption of AT1 receptor
functions in these locations might also contribute to the defect in
urinary concentration.
With the use of standard histological methods, we and others have
previously reported that, except for occasional slight dilatation of
the renal pelvis and associated mild compression of the papilla, the
kidneys of Agtr1a /
mice
appear normal (17, 26). However, the length and the nonlinear shape of
the murine inner medulla hinder its complete visualization by standard
methods of histological sectioning. In the current study, we have used
magnetic resonance microscopy to provide a detailed characterization of
the size and shape of the kidney in
Agtr1a
/
mice. Although
the areas of the renal cortex plus outer stripe were similar between
the groups, the areas of inner stripe plus the inner medulla are
smaller in
/
mice compared with controls, but this
difference is not statistically significant. Also, the linear distance
from the kidney surface to the tip of the papilla is significantly,
albeit modestly, shorter in Agtr1a
/
mice than in controls. In the wild-type controls, this
distance determined by magnetic resonance microscopy is in general
agreement with previous histomorphological measurements in mouse
kidneys (14).
Although the size and length of the inner medulla in mammals generally
correlate with urinary concentrating capacity (1, 30), the contribution
of the modest structural abnormality to the urinary concentrating
defect in Agtr1a /
mice
is difficult to quantify directly. Our findings would suggest that, if
this structural abnormality plays any role in this concentrating
defect, it is minor. First, the magnitude of the defect in
Agtr1a
/
mice is greater
than would be expected given the modest structural change. This is in
contrast to mice with combined
AT1A-AT1B
receptor deficiency in which the renal papilla is markedly atrophic and the animals have a profound inability to concentrate their urine that
is much more severe than animals lacking only
AT1A receptors (25). Furthermore,
pharmacological blockade of AT1
receptors in wild-type mice produces a urinary concentrating defect
that is similar in magnitude to that seen in
Agtr1a
/
mice. Because losartan causes no additional impairment of urinary concentration in
Agtr1a
/
mice,
AT1B receptors appear to play
essentially no role in the physiology of this process.
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ACKNOWLEDGEMENTS |
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We thank Norma Turner for secretarial assistance, Kamie Snow for technical assistance, and Dr. Nobuyuki Takahashi for thoughtful review of this manuscript.
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FOOTNOTES |
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These studies were supported by National Institutes of Health (NIH) Grants GM-20069, HL-49277, HL-56122, and DK-38108 and by the Research Service of the Department of Veterans Affairs. Magnetic resonance microscopy was performed at the Duke Center for In Vivo Microscopy, an NIH/NCRR National Resource (P41 05959). M. J. Oliverio performed these studies with the support of NIH Clinical Investigator Award DK-02449.
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.
Address for reprint requests and other correspondence: T. M. Coffman, Rm. B3002/Nephrology (111I), VA Medical Center, 508 Fulton St., Durham, NC 27705 (E-mail: tcoffman{at}acpub.duke.edu).
Received 13 July 1998; accepted in final form 25 August 1999.
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