| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1Department of Physiology, Louisiana State University Health Sciences Center, and 2Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana
Submitted 30 June 2005 ; accepted in final form 1 December 2005
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
afferent arteriole; efferent arteriole; juxtamedullary nephron; candesartan; norepinephrine
Previously, utilizing immunohistochemical approaches and an antibody that recognizes AT1A and AT1B receptor subtypes, we demonstrated the localization of the renal vascular AT1 receptor protein; these studies revealed the presence of the AT1 receptor on afferent and efferent arterioles (6) and are consistent with existing functional data (5). Similar results were obtained using an AT1A receptor-specific antibody (32) or targeted replacement of the AT1A receptor loci by the lacZ gene (19). RT-PCR analysis of AT1A and AT1B receptor mRNA in microdissected segments also indicates expression of AT1A and AT1B receptors on the afferent arteriole and glomerulus (20). However, the AT1A and AT1B receptor protein expression patterns and their differential contributions to ANG II functional responses of the efferent arteriole are not known.
The degree to which the AT1A and AT1B receptors are involved in the renal vasoconstrictor response to ANG II or the extent of differential regulation of expression of the two receptor subtypes is unclear. Determination of the functional responses of these two subtypes is not possible using pharmacological inhibitors, because those available do not distinguish between the AT1A and AT1B receptors. In this respect, AT1A receptor-deficient (AT1A–/–) mice have provided important insights into the renal vasoconstrictor actions of ANG II (5, 25). Our previous study (5), performed in kidneys from AT1A–/– mice, suggests that the vasoconstrictor response to ANG II is mediated by AT1A and AT1B receptors in the afferent arteriole, which is consistent with the mRNA expression pattern. The conclusion was based on the finding that the vasoconstrictor response to ANG II in afferent arterioles of kidneys from AT1A–/– mice was attenuated, but not abolished, presumably because of the presence of the AT1B receptor. Surprisingly, the efferent arteriole of kidneys from AT1A–/– mice did not respond to ANG II. Therefore, these results suggested that AT1A is the only AT1 receptor expressed on the efferent arteriole. In the present study, vascular responses to norepinephrine were determined in afferent and efferent arterioles of kidneys from AT1A–/– mice to test the hypothesis that the full vasoconstrictor potential of these arterioles is not altered. Similar responsiveness to norepinephrine in wild-type (WT) and AT1A–/– mice would indicate that the reduced responsiveness to ANG II in the absence of the AT1A receptor is not just a reflection of impaired overall vasoconstrictor ability of the arteriolar vascular smooth muscle cells but, rather, is specific to reduced AT1 receptor signaling. Additionally, studies were designed to further address the contribution of the AT1A and AT1B receptors to the vasoconstrictor responses of afferent and efferent arterioles to ANG II. Specifically, we tested the hypothesis that efferent arteriolar vasoconstrictor responses to ANG II are fully expressed in kidneys of mice lacking the AT1B receptor (AT1B–/–), whereas the afferent arteriolar response would be attenuated. In addition, because in our previous study (5) the afferent arteriolar response to 10 nM ANG II was reduced by 40% and the efferent arteriolar response was completely absent in kidneys of AT1A–/– mice, responses to a 10-fold higher concentration of ANG II were investigated to determine the maximal response of the AT1B receptor in AT1A–/– mice. Studies were carried out using the mouse in vitro blood-perfused juxtamedullary nephron technique, which allows for direct video-microscopic visualization of afferent and efferent arteriolar diameters studied in situ in kidneys obtained from mice with gene-targeted deletion of the AT1A or AT1B receptor.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
|
Rats were anesthetized with pentobarbital sodium (70 mg/kg ip) and subjected to bilateral nephrectomy. The rat was exsanguinated via a carotid arterial cannula into a heparinized syringe. Blood was processed to remove leukocytes and platelets as we previously described (5). After completion of all microdissection procedures, the Tyrode perfusate was replaced with the reconstituted rat blood (hematocrit 0.20). Renal arterial perfusion pressure was measured using a pressure transducer (model P23XL-1, Becton Dickinson) and amplified (models DA100C and TCI100, BIOPAC Systems, Goleta, CA). Pressure was maintained at 95 mmHg by continual adjustment of the regulator on the 95% O2-5% CO2 tank that pressurized the blood reservoir. The perfusion chamber was warmed, and the tissue surface was continuously superfused with an albumin-containing (10 g/l) Tyrode solution at 37°C. All vasoactive and pharmacological agents were administered by addition to this bathing solution. The chamber was secured to an upright fixed-stage light microscope (model E600FN, Nikon) equipped with long working distance dry (x10/0.30L) and water immersion (x40/0.80W) objectives and a variable-magnification changer (x1, x1.25, x1.5, and x2.0). The tissue was transilluminated using a 100-W halogen lamp (Nikon). The image of the vessel of interest was focused continuously using a remote focusing controller (model 99643, Nikon) and transmitted via a high-resolution Newvicon camera (model NC-70, Dage-MTI of NC, Michigan City, IN) through a time-date generator (model WJ-810, Panasonic) and video processor (model CVG-SP40, Comprehensive Video Group, S. Hackensack, NJ) and displayed on a monochrome monitor (model WV-BB 1410, Panasonic). The video signal was recorded on video tape (model SV0-3500MD, Sony) or digital video disk (model DVDR75/17, Philips) for careful analysis at a later time. Afferent and efferent arterioles were studied using the x40 water immersion objective in addition to a x1.5 or x2.0 magnifying lens, which resulted in a final magnification of x1,400 or x1,700, respectively, on the monitor. Afferent arterioles were studied at a site 25–50% along the length from the glomerulus. Efferent arterioles were studied near the glomerulus before peritubular capillary branching. Experimental protocols were begun after a 
15-min stabilization period. In some kidneys, the protocols were repeated, and another afferent or efferent arteriole was visualized and recorded. Only one kidney was studied from each animal.
Afferent and efferent arteriolar responses to norepinephrine in AT1A–/– and WT mice. We previously reported that afferent arteriolar constrictions to ANG II were attenuated and efferent arteriolar responses were absent in kidneys from AT1A–/– compared with WT mice (5). To determine the arteriolar vasoconstrictor potential of renal arterioles from AT1A–/– and WT mice, afferent and efferent arteriolar diameters were measured during superfusion with norepinephrine. After a stabilization period, afferent or efferent arteriolar luminal diameter was monitored under baseline conditions (5 min) and during sequential exposure to increasing concentrations (0.1, 0.3, and 1.0 µM) of norepinephrine (5 min at each concentration). A 15-min recovery period followed. In some kidneys [AT1A–/– (n = 7) and WT (n = 6)], a second norepinephrine protocol was performed after a recovery period.
Afferent and efferent arteriolar responses to 100 nM ANG II in AT1A–/– and WT mice. Because we previously observed that afferent arteriolar constrictions to 10 nM ANG II were attenuated and efferent arteriolar responses were absent in kidneys from AT1A–/– compared with WT mice (5), afferent and efferent arteriolar diameters of AT1A–/– and WT mice were measured during superfusion with a 10-fold higher concentration of ANG II to determine the maximal ANG II-induced AT1B receptor-mediated vasoconstriction. After recovery from the norepinephrine protocol, afferent or efferent arteriolar luminal diameter was monitored under baseline conditions (5 min), during exposure to 100 nM ANG II (5 min), and during a recovery period (5 min). In some kidneys [AT1A–/– (n = 5) and WT (n = 5)], a second ANG II protocol was performed after a recovery period.
Afferent and efferent arteriolar responses to ANG II in AT1B–/– and WT mice. Renal microvascular responsiveness to ANG II was determined in kidneys of mice lacking the AT1B receptor. After a stabilization period, afferent or efferent arteriolar luminal diameter was monitored under baseline conditions (5 min) and during sequential exposure to increasing concentrations (0.1, 1.0, and 10 nM) of ANG II (5 min at each concentration) in kidneys of AT1B–/– and WT mice. A 10-min recovery period followed. In some AT1B–/– (n = 6) and all WT kidneys, a second ANG II protocol was performed after the recovery period. We previously reported that mouse afferent arteriolar responses to first and second applications of increasing concentrations of these doses of ANG II did not differ significantly (5). In one each of the AT1A–/– and WT kidneys, a third protocol was performed after the recovery period.
Afferent and efferent arteriolar responses to ANG II before and after AT1 receptor blockade in AT1B–/– mice. To determine whether the afferent and efferent arteriolar ANG II vasoconstrictions observed in kidneys of AT1B–/– mice are mediated by an AT1 receptor, responses to ANG II were observed before and after blockade of the AT1 receptor (n = 8) in the same vessel. After a stabilization period, afferent or efferent arteriolar luminal diameter was monitored under baseline conditions (5 min) and during sequential exposure to increasing concentrations (0.1, 1.0, and 10 nM) of ANG II (5 min at each concentration). A 10-min recovery period followed. Kidneys were then superfused for 5 min with an AT1 receptor blocker (4 µM candesartan), and the ANG II concentration-response relation was repeated in the same vessel. Only one vessel was studied from each kidney.
Reagents. Norepinephrine (norepinephrine bitartrate injection, 1 mg/ml; catalog no. L-680, Levophed, Abbott Laboratories) was diluted in Tyrode solution on the day of the experiment to achieve a final concentration of 1 µM. Serial dilutions were performed to achieve 0.3 and 0.1 µM norepinephrine. Human ANG II (catalog no. 002-12, Phoenix Pharmaceuticals) was dissolved in 0.9% NaCl at 1 mM, stored at –20°C, and diluted on the day of the experiment in Tyrode solution to achieve a final concentration of 100 or 10 nM. Serial dilutions were performed to achieve 1.0 and 0.1 nM ANG II.
Data analysis. Renal arterial perfusion pressure and vessel diameters were sampled at 1 Hz and converted to digital form using a computer (Intel Pentium 4 at 2.8 GHz, Optiplex GX260, Dell Computer), analog-to-digital data-acquisition unit (model MP100ACE, BIOPAC Systems), and analysis software (AcqKnowledge 100W, version 3.7.3, BIOPAC Systems) as we previously described (31). Afferent and efferent arteriolar luminal diameters were measured manually and continuously throughout the protocol at a single site along the length of the selected vessel using a digital image-shearing monitor (model 908, Vista Electronics, Ramona, CA). This device, which was calibrated using a stage micrometer (smallest division = 10 µm), yielded diameter measurements reproducible to within <0.1 µm. The average diameter (µm) during the control (5 min), treatment (5 min), and recovery (final 5 min) periods was used for statistical analysis. Statistical analyses were performed on the raw data by one-way repeated-measures or two-way analysis of variance followed by Dunnett's test or paired t-test as appropriate. Because of the significant difference in baseline efferent arteriolar diameters between WT and AT1A–/– mice, two-way analysis of variance was conducted on the percent change from control for the efferent arteriolar responses to norepinephrine for WT vs. AT1A–/– mice. Baseline diameters of afferent and efferent arterioles between groups were analyzed by unpaired t-test. Statistical analysis was performed using a statistical software program (Sigma Stat 3.0, SPSS, Chicago, IL). P < 0.05 was considered statistically significant. Values are means ± SE (n = number of arterioles or number of mice as appropriate).
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
Afferent and efferent arteriolar responses to norepinephrine in AT1A–/– and WT mice. Afferent arteriolar baseline diameters were not significantly different between AT1A–/– (n = 7) and WT (n = 8) mice, averaging 13.1 ± 0.9 and 12.9 ± 1.4 µm, respectively, as reported previously by us (5) (Fig. 2A) and others (9). Norepinephrine produced a rapid and significant constriction in afferent arterioles of AT1A–/– and WT mice (Fig. 2A). The norepinephrine-induced afferent arteriolar constriction was not different between AT1A–/– and WT mice (P = 0.12). Afferent arteriolar diameter of AT1A–/– mice decreased 10 ± 2, 24 ± 6, and 40 ± 8% in response to 0.1, 0.3, and 1.0 µM norepinephrine, respectively (P < 0.05; Fig. 2B). In WT mice, afferent arteriolar diameter decreased 12 ± 3, 29 ± 4, and 51 ± 6%, respectively, in response to the same concentrations of norepinephrine (P < 0.05; Fig. 2B). Maximal afferent arteriolar contractions to 1,000 nM norepinephrine were 22% less in AT1A–/– than WT mice, although this was not statistically significant (P = 0.23). The vasoconstrictor responses of afferent arterioles of AT1A–/– and WT mice to 0.1–1.0 µM norepinephrine were not significantly different, indicating that the vasoconstrictor potential of the preglomerular vascular smooth muscle cells is not altered by the absence of AT1A expression.
|
Efferent arteriolar baseline diameters were significantly larger in kidneys from AT1A–/– (n = 10) than WT mice (n = 8), averaging 17.3 ± 1.4 and 11.7 ± 0.4 µm, respectively (Fig. 3A). The larger baseline efferent arteriolar diameter of AT1A–/– mice is in agreement with our previous findings (5). Efferent arteriolar diameters were significantly decreased in response to increasing concentrations of norepinephrine in AT1A–/– and WT mice. The norepinephrine-induced efferent arteriolar constriction was not different between AT1A–/– and WT mice (P = 0.26). Efferent arteriolar diameter decreased by 6 ± 1, 12 ± 3, and 29 ± 6% in AT1A–/– mice and by 6 ± 1, 17 ± 2, and 38 ± 3% in WT mice during exposure to 0.1, 0.3, and 1 µM norepinephrine, respectively (Fig. 3B). Maximal efferent arteriolar contractions to 1,000 nM norepinephrine were 24% less in AT1A–/– than WT mice, but this difference did not reach statistical significance (P = 0.23). Therefore, the lack of an effect of ANG II on efferent arteriolar diameter of AT1A–/– mice does not reflect an inability of vascular smooth muscle cell contraction. Diameters of afferent and efferent arterioles of AT1A–/– and WT mice returned to values not different from baseline on removal of norepinephrine.
|
|
|
|
Afferent and efferent arteriolar responses to ANG II before and after AT1 receptor blockade in AT1B–/– mice. The AT1 receptor antagonist candesartan alone did not alter afferent (n = 4) or efferent (n = 4) arteriolar diameters (102 and 100% of control) of AT1B–/– mice. Blockade of the AT1 receptor with candesartan completely prevented the afferent and efferent arteriolar vasoconstrictor responses to ANG II in kidneys from AT1B–/– mice (Figs. 5B and 6B). These data indicate that the ANG II-induced vasoconstrictions of afferent and efferent arterioles of AT1B–/– mice are mediated by the remaining AT1A receptor and that ANG II administration in the presence of AT1 receptor blockade does not produce an AT2 receptor-mediated renal vasodilation in AT1B–/– mice.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
We previously reported (5) that the vasoconstrictor response of afferent arterioles of AT1A–/– and WT mice to low doses (0.1 and 1 nM) of ANG II is not different; however, the vasoconstrictor response of AT1A–/– mice to high-dose (10 nM) ANG II is only 60% of the magnitude of the response of WT mice. The aim of the present study was to determine the maximal afferent arteriolar AT1B receptor response to ANG II. Two possibilities were considered: AT1B receptors may have a maximal vasoconstrictor effect that was observed at 10 nM ANG II or may constrict further to 100 nM ANG II, demonstrating a powerful vasoconstrictor potential of the AT1B receptor on the renal preglomerular vessels. In the present study, we found that the magnitude of the response of afferent arterioles of AT1A–/– mice to 100 nM ANG II was only 25% of the response of WT mouse kidneys. Responses of afferent arterioles of AT1A–/– and WT mice to 0.1 and 1 nM ANG II were not significantly different (5). Therefore, there does not appear to be a shift in the dose-response curve to ANG II of the afferent arteriole of AT1A–/– mice but, rather, a suppressed maximal vasoconstrictor response, which is mediated by the single effect of the AT1B receptor.
Efferent arterioles of AT1A–/– mice did not respond to ANG II at any dose in our previous study (5). The aim of the present study was to determine whether higher doses of ANG II are required to stimulate potentially low-abundance AT1B receptors on the efferent arteriole. If higher doses of ANG II caused efferent arteriolar vasoconstriction in AT1A–/– mice, one possible explanation would be that the AT1B receptor is present on the afferent arteriole, but in much smaller numbers. However, efferent arterioles of AT1A–/– mice did not respond to 100 nM ANG II, supporting our hypothesis that the efferent arteriole expresses only the AT1A receptor.
Our finding of a lack of functional expression of the AT1B receptor in the mouse juxtamedullary efferent arteriole is difficult to reconcile with the recent work of Helou et al. (8). They reported that the thick muscular juxtamedullary efferent arterioles, which terminate as vasa recta of the rat kidney, express AT1A, AT1B, and AT2 receptor mRNA, whereas the thin juxtamedullary efferent arterioles, which terminate as peritubular capillaries, express only the AT1A and AT2 types, and at a much lower level (8). Helou et al. also reported a reduced ANG II-induced intracellular calcium concentration response in thin and thick juxtamedullary efferent arterioles that was blocked by an angiotensin receptor blocker, valsartan (8). Also, the ANG II-induced calcium responses were similar in afferent and efferent arterioles of a given nephron (7). It is interesting to note that juxtamedullary efferent arterioles of the rat and mouse kidney that lie on the innermost surface of the cortex give rise to peritubular capillaries and vasa recta. Therefore, it is possible that our functional studies of juxtamedullary efferent arterioles are not representative of the two subpopulations of vessels studied by morphological identification and microdissection. Alternatively, there may be a species difference in the expression profile of AT1A and AT1B receptors on the muscular juxtamedullary efferent arterioles of the mouse and rat kidney.
In a very careful light- and electron-microscopic evaluation of renal arteries in WT and AT1A–/– mice, Inokuchi et al. (10) found that interlobular and afferent arterioles possessed an occasional abluminal overpopulation of vascular smooth muscle cells, increased wall thickness, and proximal expansion of renin-producing cells. They stated that the vascular smooth muscle cells of AT1A–/– mice clearly possess a contractile, but slightly synthetic phenotype compared with WT mice (10). An assessment of ultrastructure of the efferent arterioles of AT1A–/– mice was not reported in this study. Interestingly, overpopulation of vascular smooth muscle cells was specific to the intrarenal arteries (10). It is possible that these alterations in vascular structure may contribute to altered arteriolar function in AT1A–/– mice. However, we previously showed that afferent arteriolar responses to increases in renal perfusion pressure to 160 mmHg are preserved in AT1A–/– mice, with maximal responses yielding a 30% reduction in vessel diameter, which was not different from the responses in WT mice (5). To test the hypothesis that the reduced ANG II response observed in the afferent and efferent arterioles of AT1A–/– mice is not due to vascular smooth muscle cell developmental abnormalities, afferent and efferent arteriolar maximal vasoconstrictor responses were determined in response to norepinephrine. In the present study, we found that the norepinephrine-induced vasoconstrictor responses of afferent and efferent arterioles of AT1A–/– mice were not significantly different from those of WT mice. Therefore, the increased expression of renin and smooth muscle cell hyperplasia in the AT1A–/– afferent arteriole (24) does not appear to significantly affect the vasoconstrictor response to norepinephrine in this vessel. Unexpectedly, the afferent arteriolar responsiveness to norepinephrine in AT1A–/– mice was significantly reduced with aging. The mechanism of the suppressed vasoconstriction of afferent arterioles to norepinephrine in 1-yr-old AT1A–/– mice was not addressed in detail in the present study. It can be speculated that the degree of renin expression and smooth muscle cell hyperplasia may be altered with age and affect contractions to norepinephrine. In addition, the observance of a strong vasoconstriction of the efferent arteriole in the AT1A–/– mouse, in response to norepinephrine, indicates that the vascular smooth muscle cells are capable of vasoconstriction in response to another agonist. This is in agreement with the findings of Ryan et al. (26), who reported that the vasoconstrictor response to phenylephrine, U-46619, KCl, and 5-hydroxytryptamine in the isolated carotid artery was not altered in AT1A–/– compared with WT mice. Therefore, we conclude that the reduced vasoconstrictor response of the pre- and postglomerular vessels to ANG II in AT1A–/– mice is not solely limited by vascular smooth muscle cell contractile function, as assessed by norepinephrine, but is due to the loss of AT1A receptor function. Therefore, the suppressed afferent and absent efferent arteriolar response to ANG II in AT1A–/– mice appears to reflect the loss of AT1A receptor-mediated contraction specifically, rather than a global reduction in vasoconstrictor potential.
To directly assess the renal microvascular vasoconstrictor response of the AT1A receptor, we studied the diameter of afferent and efferent arterioles of AT1B–/– mice during application of ANG II. Because our earlier work supported the concept that AT1A and AT1B receptors are located on the afferent arteriole, we hypothesized that the afferent arteriolar vasoconstrictor response would be attenuated in the AT1B–/– mouse kidney. In addition, we expected that efferent arteriolar ANG II responses in AT1B–/– mice would be identical to those in WT mice if the AT1A receptor was the only subtype expressed on the efferent arteriole. To our surprise, the ANG II responses were almost identical in afferent and efferent arterioles of AT1B–/– and WT mice. Because the afferent and efferent arteriolar vascular smooth muscle cells of AT1B–/– mice responded to ANG II to the same degree as WT mice, the vasoconstrictor responses to norepinephrine were not conducted in the AT1B–/– mice. There are two possible explanations for the lack of an attenuation of the afferent arteriolar response to ANG II in the AT1B–/– mice: 1) The AT1B receptor compensates for the loss of the AT1A receptor in AT1A-null mice, and the observed response to ANG II reflects this enhancement. 2) The AT1A receptor expression may be enhanced in the absence of the AT1B receptor, as evidenced by the maximal ANG II responses of the AT1A receptors in AT1B–/– mice. There is evidence that the AT1B receptor compensates in the absence of the AT1A receptor by the small systemic pressure response to ANG II in AT1A–/– mice treated chronically with angiotensin-converting enzyme inhibition (22) and due to the difference in severity of AT1A null vs. AT1A/AT1B double-null renal phenotype. Taken together, there is strong evidence for mediation of ANG II-induced afferent arteriolar vasoconstriction by the AT1A and AT1B receptors, in addition to evidence for protein and mRNA expression of both subtypes on the afferent arteriole. The full recovery of the efferent arteriolar vasoconstrictor response to ANG II in the AT1B–/– mice supports the segmentally specific localization of the AT1A receptor as the only AT1 receptor subtype functionally expressed on the efferent arteriole of mouse juxtamedullary nephrons.
Functional and histological localization of the AT1A receptor to the renal arterioles has been reported by Kimura et al. (15) using targeted replacement of the AT1A receptor loci by the lacZ gene. The AT1A receptor was localized in the afferent and efferent arterioles of heterozygous mutant mouse kidney (15). ANG II similarly constricted the afferent and efferent arterioles of WT and heterozygous mice, but the responses were absent in homozygous-null hydronephrotic mice, arguing against AT1B receptor-mediated ANG II constriction (15). Our finding of AT1A and AT1B receptor function on the afferent arteriole is not in agreement with this argument (15) and may reflect an alteration in AT1B receptor function during the induction of hydronephrosis in AT1A receptor-null mice.
As has been shown previously in the rat kidney (4, 7, 15), the degree of afferent and efferent arteriolar ANG II vasoconstriction in WT and AT1B–/– mice was quite similar in magnitude and does not indicate a greater sensitivity of efferent than afferent arterioles to ANG II. Also, ANG II receptor blockade with candesartan completely blocked the ANG II constrictions in the AT1B–/– mice. We previously reported that candesartan blocks the ANG II-induced vasoconstriction in WT and AT1A–/– mice (5). In all genotypes studied, there was no evidence for afferent or efferent arteriolar vasodilation in response to ANG II in the presence of AT1 receptor blockade. Therefore, our results do not support AT2 receptor-mediated vasodilation in afferent or efferent arterioles in the isolated perfused mouse kidney.
In agreement with our previous study (5), we have demonstrated a significant difference in baseline efferent arteriolar diameter between AT1A–/– and WT mice. Baseline efferent arteriolar diameter was 48% larger in AT1A–/– than WT mice. Therefore, AT1A receptor deletion affects baseline efferent arteriolar diameter and may reflect an effect of ANG II on arteriolar structure and/or allowance of a greater influence of vasodilator agents. Baseline diameters of afferent arterioles of AT1A–/– mice, as well as afferent and efferent arterioles of AT1B–/– mice, were not different from those of WT mice. Therefore, expression of the AT1A receptor in the presence of a deletion of the AT1B receptor restored the normal efferent arteriolar diameter.
Overall, our functional data on the vasoconstrictor response to ANG II in AT1A and AT1B receptor-null mice indicate that the AT1A receptor is the predominant renal microvascular AT1 receptor subtype. There does appear to be compensation for the vasoconstrictor response to ANG II by the AT1A and AT1B receptors when the other subtype is not present. In contrast, Zhou et al. (33) showed that the vasoconstrictor response to ANG II is unaltered in the abdominal aorta and femoral artery of AT1A–/– compared with WT mice, suggesting that the response is mediated predominantly by the AT1B receptor. These findings have not been confirmed in the AT1B–/– mice. Therefore, there appears to be a heterogeneity in the expression profile of the AT1A and AT1B receptors within the renal microcirculation, as well as in the systemic circulation. We conclude that the AT1A and AT1B receptors mediate the afferent arteriolar vasoconstriction to ANG II, whereas the AT1A receptors alone mediate the efferent arteriolar responses to ANG II.
|
GRANTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
Portions of this work have been published in abstract form (FASEB J 18: A288, 2004; FASEB J 19: A1144, 2005).
|
FOOTNOTES |
|---|
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. Section 1734 solely to indicate this fact.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  K. Machura, D. Steppan, B. Neubauer, N. Alenina, T. M. Coffman, C. S. Facemire, K. F. Hilgers, K.-U. Eckardt, C. Wagner, and A. Kurtz Developmental renin expression in mice with a defective renin-angiotensin system Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1371 - F1380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Razga and J. R. Nyengaard Up- and down-regulation of angiotensin II AT1-A and AT1-B receptors in afferent and efferent rat kidney arterioles Journal of Renin-Angiotensin-Aldosterone System, December 1, 2008; 9(4): 196 - 201. [Abstract] [PDF]
|
|
|
|
|
|
S. Park, B. J. Bivona, Y. Feng, E. Lazartigues, and L. M. Harrison-Bernard Intact renal afferent arteriolar autoregulatory responsiveness in db/db mice Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1504 - F1511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Park and L. M. Harrison-Bernard Augmented Renal Vascular nNOS and Renin Protein Expression in Angiotensin Type 1 Receptor Null Mice J. Histochem. Cytochem., April 1, 2008; 56(4): 401 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. C. Li, L. G. Navar, Y. Shao, and J. L. Zhuo Genetic deletion of AT1a receptors attenuates intracellular accumulation of ANG II in the kidney of AT1a receptor-deficient mice Am J Physiol Renal Physiol, August 1, 2007; 293(2): F586 - F593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Park, B. J. Bivona, and L. M. Harrison-Bernard Compromised renal microvascular reactivity of angiotensin type 1 double null mice Am J Physiol Renal Physiol, July 1, 2007; 293(1): F60 - F67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Shen, L. M. Harrison-Bernard, A. J. Fuller, V. Vanderpool, Z. Saifudeen, and S. S. El-Dahr The Bradykinin B2 Receptor Gene Is a Target of Angiotensin II Type 1 Receptor Signaling J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1140 - 1149. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
, n = 7) and wild-type (WT, 
, n = 8) mice. Norepinephrine produced a significant vasoconstriction in both groups. Baseline diameters were not significantly different. *P < 0.05 vs. baseline.
P < 0.05 vs. WT.
, n = 7 AT1A–/– and 
, 5 WT) and efferent (
, 7 WT) arteriolar diameter responses to 100 nM ANG II in AT1A–/– and WT mice. ANG II produced a significant vasoconstriction in afferent arterioles of both groups; response was reduced in AT1A–/– compared with WT mice. Efferent arterioles of WT mice constricted in response to ANG II; vessels from AT1A–/– mice did not. *P < 0.05 vs. baseline. 
