1 Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and 2 Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria 3052, Australia
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ABSTRACT |
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The intrarenal expression of
angiotensin II (ANG II) type 1 (AT1) receptors and
angiotensin-converting enzyme (ACE) was determined in ANG II-induced
hypertensive rats (80 ng/min; 2 wk). Systolic blood pressure averaged
184 ± 3 and 125 ± 1 mmHg in ANG II-infused compared with
Sham rats on day 12. Total kidney AT1 receptor
protein levels were not altered significantly. AT1 receptor
binding mapped by quantitative in vitro autoradiography was
significantly decreased in glomeruli (172 ± 25 vs. 275 ± 34 disintegrations · min1 · mm
2)
and the inner stripe of the outer medulla (121 ± 17 vs. 178 ± 19 disintegrations · min
1 · mm
2), but not proximal convoluted tubules (48 ± 9 vs. 58 ± 6 disintegrations · min
1 · mm
2)
of ANG II-infused compared with Sham rats. Proximal tubule ACE binding
was significantly augmented (132 ± 4 vs. 97 ± 3 disintegrations · min
1 · mm
2)
in ANG II-infused rats. In summary, during ANG II-induced hypertension, glomeruli and inner stripe of the outer medulla have reduced
AT1 receptor binding. Proximal convoluted tubules exhibit
maintained AT1 receptor density and increased ACE binding,
which together with the elevated ANG II levels suggest that ANG II
exerts a sustained influence on tubular reabsorption and consequently
contributes to the development and maintenance of ANG II-dependent hypertension.
Western blot analysis; glomeruli; proximal convoluted tubules; outer medulla; in vitro autoradiography; osmotic minipump
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INTRODUCTION |
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HYPERTENSION INDUCED BY CHRONIC infusion of angiotensin II (ANG II) is a useful experimental model of ANG II-dependent hypertension. Although the mechanisms responsible for the progressive nature of ANG II-induced hypertension are incompletely understood, accumulating evidence indicates that elevated intrarenal ANG II levels play a critical role in the development and maintenance of high blood pressure in this model. The augmented intrarenal ANG II levels may be due to a renin-independent pathway for intrarenal ANG II formation because renal renin content and mRNA expression are markedly suppressed (20) and kidney angiotensinogen mRNA and protein levels (9, 10) are elevated in ANG II-infused rats. Elevated intrarenal ANG II levels may also occur by AT1 receptor-mediated uptake and accumulation of circulating ANG II (32, 34). AT1 receptor-mediated endocytosis is also required for apical ANG II-mediated proximal tubule sodium transport (17). These data suggest that ANG II may be actively taken up through AT1 receptor-mediated endocytosis into intracellular sites that protect ANG II from degradation and metabolism and may provide a mechanism for the continued actions of intrarenal ANG II in the development of hypertension.
Although it is well recognized that vascular and glomerular ANG II receptors are downregulated during various conditions that increase systemic and intrarenal ANG II levels, proximal tubule AT1 receptors appear to be less sensitive. Early studies by Douglas (5) demonstrated that glomerular ANG II receptors were downregulated by high ANG II concentrations, whereas tubular epithelial ANG II receptors were upregulated by high levels of ANG II. Amira and Garcia (2) reported that glomerular ANG II receptors are decreased in 2K1C hypertensive rats, whereas preglomerular vascular ANG II receptors are reduced after a low-sodium diet (1). Cheng et al. (3) demonstrated that glomerular AT1 mRNA levels were decreased, whereas proximal tubule AT1 mRNA levels were increased, in rabbits fed a low-salt diet. AT1 receptor mRNA levels in these tissues were reversed by chronic angiotensin-converting enzyme (ACE) inhibition (3). In addition, Wang et al. (23) reported that kidney AT1A and AT1B receptor mRNA levels were reduced by chronic ANG II infusion at doses that did not alter blood pressure. It is not clear how glomerular and tubular ANG II receptor expression are altered in a model of chronic ANG II infusion that results in sustained hypertension.
The present study was designed to determine whether the expression of kidney AT1 receptors is differentially regulated during the development of ANG II-induced hypertension. Specifically, we examined the effects of chronic ANG II infusion on kidney AT1 receptor protein expression. Second, we employed in vitro autoradiography to localize and quantitate changes in glomerular, proximal convoluted tubular, and medullary ANG II receptor binding during chronic ANG II infusion. In addition, ACE binding was performed to complement our previous findings of enhanced renal ACE activity in ANG II-dependent hypertension.
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MATERIALS AND METHODS |
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Animals and tissue preparation. Male Sprague-Dawley rats (222 ± 3 g; n = 47) (Charles River Labs, Wilmington, MA) were housed in individual wire cages and maintained in a temperature-controlled room regulated on a 12:12-h light-dark cycle. All animals were fed a standard rat chow (Ralston-Purina) and had free access to tap water. To produce ANG II-induced hypertension, rats were anesthetized with pentobarbital sodium (60 mg/kg ip) and an osmotic minipump (model 2002; Alza) was implanted subcutaneously at the dorsum of the neck. Rats received chronic ANG II infusion (80 ng/min; Novabiochem) for 3 (n = 8), 6 (n = 7), or 13 (n = 8) days. Additional rats underwent sham surgery and were studied at 3 (n = 9), 6 (n = 8), or 13 (n = 7) days for comparison. Systolic blood pressure was measured in conscious rats 1 day before implantation of a minipump and on days 3, 6, and 12 after the beginning of the ANG II infusion, using tail-cuff plethysmography (model 52-0338; Harvard Apparatus).
Trunk blood from rats after rapid decapitation was collected into chilled tubes containing EDTA (5 mM) for determination of plasma renin activity (PRA). Plasma was separated by centrifugation, collected, and stored atWestern blot analysis of whole kidney AT1 receptor protein. Proteins were extracted from 3-, 6-, and 13-day Sham and ANG II-infused hypertensive rat kidneys after homogenization as described previously (7) and measured by the method of Lowry et al. (13). Total kidney protein extracts (50 µg) were electrophoretically separated by 3-10% stacking Tris-glycine gels at 100 V for 2 h (10% SDS, 24 mmol/l Tris base, and 192 mmol/l glycine). Proteins were subsequently transferred to nitrocellulose membranes (0.45; Bio-Rad) in transfer buffer (20% methanol, 12 mmol/l Tris base, and 96 mmol/l glycine), blocked overnight, and incubated with primary anti-peptide AT1 polyclonal antibody at 1:200 (15-24 amino acids; SC-1173, Santa Cruz) for 3 h at room temperature. Signals were detected using enhanced chemiluminescence (Amersham). Duplicate gels were prepared and stained with 0.1% Coomassie blue R250 and then destained in 7% acetic acid-5% methanol to visualize protein bands for total protein quantification and confirmation of equal protein loading between the groups at each ANG II infusion time point. The films and Coomassie blue-stained gels were scanned using Digital Imaging and Analysis Systems (Alpha Innotech).
Quantitative in vitro autoradiographic analyses of renal AT1 and AT2 receptors and ACE. To study whether ANG II receptor subtypes and ACE are differentially regulated in the kidney during ANG II-induced hypertension, renal AT1 and AT2 receptor and ACE binding were measured using quantitative in vitro autoradiography as described previously (29-31). Kidney sections were carefully cut to expose the corticopapillary axis. Twenty-micrometer frozen sections were cut on a cryostat, mounted onto glass slides, and dried under reduced pressure at 4°C overnight. All kidney sections were first preincubated in 10 mM sodium phosphate buffer, pH 7.4, for 15 min at 22°C to clear endogenous ligands. For localization and quantification of AT1 and AT2 receptors, the preincubated sections were placed in fresh volumes of the same buffer containing ~90 pM radioligand, 125I-[Sar1, Ile8]ANG II, 0.5 mg/ml bacitracin, and 0.2% BSA for 60 min at 22°C (n = 8 sections/animal). Nonspecific binding was determined in the presence of 1 µM unlabeled ANG II (n = 4 sections/animal; Hypertensin, Ciba Pharmaceutical). AT1 and AT2 receptors were measured in the presence of the AT2 receptor antagonist 10 µM PD-123319 (Parke-Davis; n = 8 sections/animal) or the AT1 receptor antagonist losartan (DuPont; n = 8 sections/animal) in the incubation buffer, respectively. For total ACE binding, sections (n = 8/animal) were incubated in fresh buffer containing 0.3 µCi/ml 125I-351A (Lisinopril; ACE inhibitor) and 0.2% BSA for 60 min at 22°C. Nonspecific binding was determined in the presence of 1 mM EDTA (n = 4 sections/animal) in parallel incubations. After incubation of tissue sections from both groups with 125I-labeled radioligands, the sections were washed, air dried, and exposed to X-ray films (Agfa-Gaevert) for 2 days (ACE) or 7 days (ANG II). The films were developed and the images were analyzed using a computerized densitometry imaging system (MCID, Imaging Research, ONT). To allow accurate quantification of the levels of ACE and AT1 and AT2 receptor binding in a defined anatomic site, a set of six radioactivity standards ranging from zero to tens of thousands counts per minute per square millimeter was included and exposed together with incubated kidney sections in each experiment. The 125I radioactivity standards were prepared by application of known amounts of 125I radioactivity to 5-mm diameter disks of 20-µm-thick rat brain stem sections mounted on gelatin-coated slides. The radioactivity of each standard was fitted to a calibration curve by the computer to convert optical density values of each pixel into disintegrations of 125I radioactivity per millimeter squared of tissue section per minute. Autoradiographic images of each kidney section were displayed on a computer screen and enlarged up to 50 times using a microscope and camera projection. This allowed quantification of structures as small as a single glomerulus or proximal convoluted tubule with the results expressed as disintegrations per minute per square millimeter of measured area relative to the computer monitor. Thus for each experiment, the radioactivity on a defined structure such as the glomerulus, proximal convoluted tubule, and the inner stripe of the outer medulla from each section could be quantitated using the same calibration curve. Consequently, the sensitivity of this technique is ~2 dpm/mm2 in a defined structure above the background level.
Consecutive tissue sections of each kidney were stained with hematoxylin-eosin and used for histological localization of the ACE and ANG II receptor binding in the glomeruli, proximal convoluted tubules, and inner stripe of the outer medulla. In the cortical parenchyma, the labyrinth and the medullary rays are readily distinguishable. The labyrinth consists mainly of the vasculature, glomeruli, and proximal convoluted tubules, whereas the medullary rays contain predominantly proximal straight tubules, distal tubules, and collecting ducts. The distal tubules and collecting ducts constitute a minor portion of the cortex compared with proximal convoluted tubules. This approach is consistent with the topographical relationships between various cortical structures as described by Kriz and Kaissling (11).Data analysis. An average of eight tissue sections was analyzed for each animal. Twenty to forty fields were sampled for the glomeruli or proximal convoluted tubules on each tissue section. The AT1 receptor binding on glomeruli was measured throughout the outer cortex as described previously (31). A single measurement of AT1 receptor binding was obtained from each tissue section for the entire inner stripe of the outer medulla, which included vasa recta bundles and interbundle areas. For ACE binding, a single measurement was made for each tissue section. Data are expressed as means ± SE. Data were analyzed by Student's t-test. P < 0.05 was considered significant.
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RESULTS |
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Systolic blood pressure.
Systolic blood pressure (SBP) was comparable in both groups before
implantation of osmotic minipumps but progressively increased in ANG
II-infused rats at 3, 6, and 12 days from 117 ± 2 to 141 ± 1, 159 ± 3 and 184 ± 3 mmHg, respectively (Fig.
1). SBP was unchanged over the same time
period in Sham animals, averaging 115 mmHg over the 2-wk period.
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PRA.
PRA averaged 4.4 ± 0.5 ng ANG
I · ml1 · h
1
(n = 23) in Sham animals. Plasma renin activity was
markedly suppressed in the ANG II-infused rats to 0.47 ± 0.19 (n = 7), 0.15 ± 0.04 (n = 7), and 0.17 ± 0.03 (n = 8) ng ANG
I · ml
1 · h
1 at 3, 6, and
13 days, respectively (P < 0.05).
Western blot analysis of kidney AT1 receptor protein.
Total kidney AT1 receptor protein (42 kDa ) levels were
maintained during ANG II-induced hypertension (3, 6, 13 days; Fig. 2). The glycosylated form of the
AT1 receptor (58 kDa) also did not change significantly
during chronic infusion of ANG II [13.5 ± 1.8 vs. 18.2 ± 1.2 densitometric units (du) for day 3, 17.4 ± 0.9 vs.
15.8 ± 1.8 du for day 6, and 24.6 ± 1.7 vs.
31.0 ± 3.3 du for day 13, Sham and ANG II,
respectively]. Densitometric analysis of a single protein band for
total kidney protein Coomassie blue-stained duplicate gels
(n = 3) averaged 63.3 ± 3.5 vs. 62.4 ± 1.0 du (~39 kDa) for day 3, 54.2 ± 2.3 vs. 46.8 ± 3.1 du (~68 kDa) for day 6, and 24.5 ± 3.2 vs.
22.5 ± 2.3 du (~57 kDa) for day 13 Sham and ANG
II-infused rats (n = 5-6 for each gel),
respectively, demonstrating equal protein loading between Sham and ANG
II-infused groups at each time point (P > 0.05).
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Autoradiographic localization and quantification of renal
AT1 and AT2 receptor binding and proximal
tubular ACE.
The effects of chronic ANG II infusion on renal AT1
receptor binding in Sham and ANG II-infused rats are shown in Figs.
3 and 4.
Because total kidney AT1 receptor protein levels were
similar between Sham and ANG II-infused rats, AT1 receptor
binding was localized and quantified in anatomically defined structures
including glomeruli and proximal convoluted tubules, as well as the
inner stripe of the outer medulla from kidneys collected at 13 days. As
previously reported, AT1 receptors were localized
predominantly in the glomeruli, inner stripe of the outer medulla, and
proximal convoluted tubules (30, 31) (Fig. 3). Chronic ANG
II infusion significantly decreased AT1 receptor binding
(Fig. 4) in glomeruli by 37% (P < 0.05) and the inner
stripe of the outer medulla by 32% (P < 0.05),
whereas AT1 receptor binding remained unaltered in the
proximal tubules (P = 0.5). In contrast,
AT2 receptor binding was not readily detectable in either
Sham or ANG II-infused hypertensive rats. There was no
125I-[Sar1,Ile8]ANG II binding in
the presence of an AT1 receptor antagonist (10 µM
Losartan). Similarly, total
125I-[Sar1,Ile8]ANG II binding
was identical to
125I-[Sar1,Ile8]ANG II binding in
the presence of 10 µM PD-123319.
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DISCUSSION |
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A constant infusion of an initially subpressor dose of ANG II produces a slowly developing hypertension in rats (6, 21, 34). Surprisingly, there is a lack of downregulation of the intrarenal renin-angiotensin system and there is augmentation of intrarenal ANG II to levels greater than can be explained on the basis of the circulating ANG II concentrations (33). Plasma renin activity and kidney renin mRNA (20) are substantially suppressed, suggesting that endogenous production of ANG II would be similarly decreased. However, during chronic infusion of a different isoform of ANG II, the endogenous levels of ANG II in the plasma and kidney were similar to those of vehicle-infused animals (32). This may be the result of elevated liver and kidney angiotensinogen mRNA and protein levels (9, 10) and enhanced renal ACE activity (20), which contribute to maintained ANG II production despite reduced renin. The combined effects of infused ANG II and sustained endogenous production of ANG II lead to elevated intrarenal ANG II levels that exert marked effects on the sodium excretory capability as manifested in a marked suppression of the pressure natriuresis relationship, leading to a lower absolute and fractional sodium excretion for any given level of arterial pressure (22). Because renal blood flow and glomerular filtration rate are less suppressed, the overall changes in sodium excretion appear to be due primarily to the effects of ANG II on tubular transport function.
Because the biological actions of ANG II are influenced by the number of ANG II receptors present, establishing the differential regulation of the intrarenal ANG II receptors in ANG II-induced hypertension is important for understanding the mechanisms responsible for the renal functional changes observed in this model. We have previously reported that kidney AT1 receptor protein and AT1A mRNA levels are not altered by chronic ANG II infusion (6). The present study confirms these observations and extends these findings to show that, earlier in the development of hypertension, kidney AT1 receptor expression is also maintained at the same level as in Sham animals. Overall kidney AT1 protein expression did not show a temporal change although blood pressure steadily increased during the 2-wk ANG II infusion period. This may help explain how the kidney continues to respond to the elevated ANG II levels. In our earlier studies, we were unable to address the regional distribution of the AT1 receptor changes because the analyses were performed on whole kidney tissue. Investigation of segmental AT1 receptor-expressing components of the kidney was performed using in vitro autoradiography because it provides a quantitative assessment of vascular and tubular AT1 receptors. Cheng et al. (3) have shown that glomerular and proximal tubule AT1 receptor mRNA levels were differentially regulated by alterations in the endogenous production of ANG II. Discordant expression of glomerular and tubular AT1 receptor expression may have been undetectable in our analysis of total kidney samples. In addition, in vitro autoradiographic binding methods evaluate mainly membrane-bound AT1 receptors, whereas Western blot analysis detects total AT1 receptor abundance, which would reflect both intracytoplasmic and membrane-bound AT1 receptors. Disparities in renal ANG II binding and AT1 mRNA expression have been shown in studies by Sechi et al. (18), in which 7-day ANG II infusion did not change renal AT1 mRNA expression but decreased ANG II receptor density. Therefore, the combined analyses of kidney protein expression and ANG II binding at different anatomic sites in the kidney allowed us to uncover the differential regulation of tubular and glomerular ANG II receptor regulation in the chronic state of elevated circulating and renal ANG II levels.
A reduction of glomerular AT1 receptors was found in ANG II-infused rats. These data are in agreement with previous reports demonstrating decreased glomerular ANG II receptor binding caused by chronic ANG II infusions (8) and during in vitro exposure to ANG II in cultured mesangial cells (14) and vascular smooth muscle cells (12). In contrast, Amiri and Garcia (1) showed that glomerular and preglomerular vascular ANG II receptor binding was unchanged by chronic ANG II infusions; however, vascular ANG II receptor binding was decreased significantly by a low-salt diet. In the above study, ANG II infusion was carried out for 7 days and blood pressure was elevated 20 mmHg. The temporal profile and magnitude of hypertension achieved were quite different compared with our study.
AT1 receptors were significantly decreased in the inner stripe of the outer medulla. AT1 receptors in the outer medulla have been localized predominantly to renal medullary interstitial cells by Zhuo et al. (27). Physiological studies have shown that ANG II influences medullary/papillary blood flow and urinary water and sodium excretion (15). AT1 receptors at this site appear to be regulated physiologically in a manner similar to those in glomerular mesangial cells (28). Dietary salt loading is associated with an increase in glomerular and inner stripe ANG II binding (26). The direct effects of ANG II acting on the AT1 receptor of renal medullary interstitial cells in culture include stimulation of protein synthesis, extracellular matrix accumulation, and increases in intracellular inositol trisphosphate and calcium concentrations (25). We have previously shown that medullary ANG II levels are much higher than cortical levels and are increased threefold by chronic ANG II infusion (21). Therefore, the effects of elevated ANG II to decrease AT1 receptor expression in the renal medulla may limit its effects on medullary blood flow modulation and/or alterations in other paracrine hormonal systems.
Although glomerular receptors and those in the inner stripe of the outer medulla AT1 were reduced by chronic ANG II infusion, we found that the proximal tubule AT1 receptor binding levels were maintained. A differential regulation of vascular and tubular AT1 receptors has also been demonstrated in rabbits on a low-sodium diet, which produces a reduction in AT1 mRNA in glomeruli and increases in proximal tubules (3). The maintained proximal tubule AT1 receptor levels are consistent with the Western blot analysis that demonstrated maintained total AT1 receptor abundance. The Western blot analysis may reflect the preponderance of proximal tubule AT1 receptors. The proximal tubule actions of ANG II have been well established. ANG II has been shown to exert powerful control over sodium transport in the proximal tubule by enhancing the affinity of the Na+/H+ antiporter (4). ANG II-induced changes in transepithelial sodium transport has also been demonstrated in opossum kidney proximal tubule cells stably transfected with the AT1A receptor (19). The proximal tubule effects of ANG II are mediated by activation of apical and basolateral AT1A receptors, which is consistent with the immunohistochemical localization of the receptor (7). Modulation of proximal tubule fluid transport by endogenously produced ANG II has been reported (16). These tubular transport effects of ANG II may participate importantly in the development of hypertension.
AT2 receptor binding was very low in both groups and was difficult to distinguish from the nonspecific binding. There were no significant differences between total and AT1 binding in a given structure in the same kidney. This low AT2 receptor binding in the adult kidney is consistent with our previous studies (30). Wang et al. (24) found that AT2 receptor protein expression was not altered by chronic ANG II infusion determined by Western blot analysis. In the present study, we were unable to assess the regulation of ANG II on renal AT2 receptors.
The present study shows that proximal tubule ACE binding was significantly elevated in ANG II-infused rats. This finding is consistent with increased kidney ACE activity reported in 2K1C and chronic ANG II-infused rats (21). This may explain how endogenous ANG II formation is maintained despite reduced renal renin content in ANG II-induced hypertension (21). Because kidney angiotensinogen mRNA levels are elevated (10) and provide an adequate source of substrate, an elevated intrarenal ACE activity may be important for enhanced intrarenal ANG II formation and the development of hypertension. The increased intrarenal ACE, which is localized primarily on the proximal tubule brush border, provides a possible mechanism for an enhanced rate of ANG II conversion in the proximal tubules, which could then act on proximal tubule AT1 receptors to maintain proximal reabsorption rate and, in this manner, contribute to the development of hypertension.
In summary, during ANG II-induced hypertension, glomeruli have reduced AT1 receptor binding, whereas proximal tubules exhibit maintained AT1 receptor density and increased ACE binding, which together with the elevated ANG II levels provides the basis for the sustained influence on proximal tubular reabsorption and consequently on the development and maintenance of ANG II-dependent hypertension.
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ACKNOWLEDGEMENTS |
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The authors acknowledge Denise F. O'Leary for technical assistance.
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FOOTNOTES |
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This work was supported by a National American Heart Association Scientist Development Grant (to L. M. Harrison-Bernard). H. Kobori was supported by fellowships from the National Kidney Foundation and the Uehara Memorial Foundation. J. Zhuo and M. Ohishi were supported by an Institute Block Grant to the Howard Florey Institute of Experimental Physiology and Medicine from the National Health and Medical Research Council of Australia.
Address for reprint requests and other correspondence: L. M. Harrison-Bernard, Dept. of Physiology SL39, Tulane Univ. Health Sciences Center, New Orleans, LA 70112-2699 (E-mail: lharris{at}tulane.edu).
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.
Received 12 December 2000; accepted in final form 24 July 2001.
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