Contribution of angiotensin II internalization to intrarenal angiotensin II levels in rats

Catherine Ingert1, Michèle Grima1,2, Catherine Coquard1, Mariette Barthelmebs1, and Jean-Louis Imbs1,2

1 Institut de Pharmacologie, Faculté de Médecine, Université Louis Pasteur; and 2 Service d'Hypertension, des Maladies Vasculaires et Pharmacologie Clinique, Hôpitaux Universitaires de Strasbourg, 67085 Strasbourg France


    ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

This study was designed to determine the involvement of AT1 receptors in the uptake of ANG II in the kidney of rats exposed to differing salt intake. Male Wistar-Kyoto rats were treated with a normal-salt (NS; 1% NaCl, n = 7) or a low-salt (LS; 0.025% NaCl, n = 7) diet combined with (LS+Los, n = 7; NS+Los, n = 7) or without losartan (30 mg · kg-1 · day-1), an AT1 receptor antagonist. Renin (RA) and angiotensin-converting enzyme (ACE) activities and angiotensinogen, ANG I, and ANG II levels were measured in plasma, renal cortex, and medulla. In LS rats, in both plasma and renal cortex, the increase in RA was associated with an increase in ANG I and ANG II levels compared with NS rats, but intrarenal ANG II levels increased more than ANG I levels. In NS+Los rats, the increase in RA in plasma was followed by a marked increase in plasma ANG I and ANG II levels compared with NS rats whereas in the kidney the increase of renal RA was followed by a decrease of the levels of these peptides. The same pattern was observed in LS+Los rats, but the decrease in renal ANG II levels was much more pronounced in LS+Los rats than in NS+Los rats. Our results suggest that the increase in renal ANG II levels after salt restriction results mainly from an uptake of ANG II, via AT1 receptors. Such elevated intrarenal ANG II levels could contribute to maintain sodium and fluid balance and arterial blood pressure during salt-deficiency states.

sodium-restricted diet; losartan; kidney; renin-angiotensin system


    INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

THE KIDNEY IS A TARGET for ANG II, and renal effects of this peptide may play a critical role in the regulation of renal hemodynamics and sodium excretion. Several groups showed that intrarenal ANG II levels are higher than the circulating levels (2, 21) and provided evidence for a differential regulation of circulating and renal angiotensins (4, 6). This was confirmed in the renal cortex and medulla (7).

The kidney contains all the necessary components of the renin-angiotensin system (RAS) to generate ANG II (1, 5, 8, 11, 19, 22), but this cannot be taken as direct evidence for local production. Indeed, local ANG II levels may depend on 1) in situ synthesis, 2) uptake of the peptides from the circulation, or 3) a combination of in situ synthesis and uptake of RAS components. In fact, extensive internalization via AT1 receptors of plasma ANG II was observed after ANG II infusions (29, 30). Nevertheless, during ANG II infusion, renin synthesis decreases in the kidney. Therefore, the part of intrarenal ANG II resulting from intrarenal synthesis is underevaluated compared with ANG II resulting from plasma uptake.

In a companion paper (11a), we showed that during sodium restriction, renal ANG II levels increased more than ANG I levels and we suggested that renal ANG II levels resulted not solely from a local synthesis from ANG I but also from an uptake of the peptide via AT1 receptors. The present study was designed to determine the involvement of AT1 receptors in the renal uptake of ANG II under conditions of low-salt intake. In this study, the different components of the RAS were measured in plasma and kidney of rats receiving a normal-sodium or a low-sodium diet combined with or without losartan, an AT1 receptor antagonist. This antagonist is able to block AT1-mediated ANG II internalization (29). Furthermore, the kidney was separated into cortex and medulla; there appear to be limited renin synthesis and high AT1 receptor levels in the renal medulla, which could be a privileged compartment for the uptake phenomenon (27).


    MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Experimental Design

Male Wistar-Kyoto rats were obtained from Iffa-Credo (l'Arbresle, France) and housed in our laboratory 1 wk before the beginning of the treatments. A 12:12-h dark-light cycle was used (lights on from 6 AM to 6 PM). Animals had free access to tap water and consumed a diet of rat chow (UAR, Epinay sur Orge, France). They were divided into four groups and treated with a normal-salt diet (NS group, 1% NaCl; n = 7), a low-salt diet (LS group, 0.025% NaCl; n = 7), a normal-salt diet + losartan (NS+Los group; n = 7) or a low-salt diet + losartan (LS+Los group; n = 7). The different salt diets (UAR 212, UAR 210) were purchased from UAR. The rats were fed a normal-salt or a low-salt diet over 10 days to accustom the animals to the food. Losartan [30 mg · kg-1 · day-1 (efficacy dose for antihypertensive effects given per gavage; Ref. 13)] was given by a single daily oral gavage during the last 8 days; an equal amount of distilled water was given by oral gavage to both the NS and LS rats. The combined treatment of sodium restriction and losartan administration lasted only 8 days, because in a previous study, we observed mortality of ~50% of the animals beyond this period (unpublished observations). All animals were 10 wk old on the day of sampling and were deprived of food but not of water the night before plasma and tissue sampling. Rats were killed by decapitation 3 h after the last gavage.

Plasma and Kidney Sampling

After decapitation, ~5 ml of trunk blood were rapidly collected into ice-cold tubes containing 0.25 ml of inhibitor cocktail [2.5 mM phenanthroline, 3 mM EDTA, 0.1 mM pepstatin, 3 µM rat renin inhibitor Ac-His-Pro-Phe-Val-Sta-Leu-Phe-NH2 (Néosystem), 0.11 mM neomycin sulfate; final concentrations] for measurement of ANG I and ANG II, 1 ml was used for plasma renin activity (PRA) and plasma angiotensinogen (EDTA tube) and 1 ml was used for ACE activity (lithium heparin tube). The blood was immediately centrifuged at 4°C for 10 min at 2,000 g. Plasma samples were frozen in liquid nitrogen and stored at -80°C until assay.

The right kidney was rapidly removed and dissected on an ice-cold plate into cortex and medulla. One-half of each tissue sample was used for measurement of ANG I and ANG II; these were weighed and homogenized in ice-cold methanol (6). The homogenates were centrifuged at 4°C for 10 min at 2,000 g, and the supernatants were evaporated to dryness and stored at -80°C. The other half of each tissue sample was used for determination of renal renin activity (RA) and homogenized in a phosphate buffer with 144 mM PMSF-10 mM phenylmercuric acetate (in ethanol) and centrifuged at 4°C for 20 min at 5,000 g. The supernatants were stored at -20°C until assay.

The left kidney was also dissected into cortex and medulla and weighed. One-half of each tissue sample was used for determination of renal angiotensinogen and homogenized in a phosphate buffer with 1.5 M ammonium sulfate, 1.5 mM pepstatin (in ethanol), and 144 mM PMSF-10 mM phenylmercuric acetate (in ethanol); the homogenate was centrifuged at 4°C for 20 min at 5,000 g, and the supernatant was decanted. To precipitate angiotensinogen, the ammonium sulfate concentration was adjusted to 2.5 M by addition of 4 M ammonium sulfate and centrifuged as described above. The ammonium sulfate precipitate was resuspended in water and stored at -20°C until assay (4). The other half of each tissue sample was frozen in liquid nitrogen; after thawing of the cortex and the medulla, Triton X-100 (0.3%) was added and the tissues were homogenized and centrifuged at 4°C for 20 min at 11,500 g after sonication. The supernatants were diluted in Triton X-100 for determination of ACE activity and stored at -20°C until assay.

Measurement of RAS Components

Plasma and renal angiotensinogen. Plasma angiotensinogen was determined by incubating diluted plasma with a phosphate buffer, a pool of exogenous rat renin, and 144 mM PMSF (in ethanol) (4). After incubation at 37°C for 60 min, ANG I generation was quantified by RIA as described below. Cortical and medullar angiotensinogen samples were incubated with a phosphate buffer, a pool of exogenous rat renin, and 144 mM PMSF-10 mM phenylmercuric acetate (in ethanol). After incubation at 37°C for 120 min, 0.5 ml of 1% trifluoroacetic acid was added; each incubation was extracted with a Sep-Pak C18 cartridge (Oasis Waters, Milford, MA), the eluate was evaporated to dryness, and ANG I was determined by RIA (4). Plasma and renal angiotensinogen are expressed as nanograms of ANG I generated per milliliter of plasma and nanograms of ANG I generated per gram of tissue weight, respectively.

Plasma and renal tissue renin activities. PRA was measured by determining the level of ANG I generated during a 30-min incubation of plasma at 37°C in the presence of 5 mM 8-hydroxyquinoline. ANG I was measured by RIA. In the cortex and the medulla, RA was measured after determination of ANG I generated during a 30-min incubation of diluted supernatants in the presence of plasma enriched in angiotensinogen obtained from rats 48 h after binephrectomy (4). ANG I was measured by RIA. PRA and tissue RA are expressed as nanograms of ANG I generated per milliliter of plasma per hour and micrograms of ANG I generated per gram of tissue weight per hour, respectively.

Plasma and renal ACE activities. ACE activity was determined in vitro with an enzymatic method. In vitro plasma and renal ACE activities were determined as described by Unger et al. (23) in the presence of an artificial substrate (10 mM N-carbobenzoxy-Phe-His-Leu, 67 mM phosphate buffer, pH 8.0, 300 mM NaCl, 10 µM ZnSO4). The dipeptide (His-Leu) produced by the reaction was measured spectrofluorimetrically after coupling with o-phthaldialdehyde. To ensure linearity of the ACE activity measurement, the protein concentration in the assay was maintained at <2 mg/ml (cortex or medulla) or <20 mg/ml (plasma) (25). ACE activity is expressed as nanomoles of His-Leu formed per minute per milligram of protein.

Plasma and renal angiotensins. Plasma angiotensins were extracted by reversible adsorption to phenylsilyl-silica (Bondelut-PH, Analytichem, Harbor City, CA), and ANG II was additionally separated from other peptides by isocratic reversed-phase HPLC (Nucleosyl 100-5C, Macherey-Nagel, Oensingen, Switzerland) according to the method of Nussberger et al. (17). ANG I and ANG II levels were quantified by RIA with rabbit anti-ANG I and anti-ANG II sera. Antibodies to ANG I and ANG II were raised in our laboratory in rabbits immunized against the peptide coupled to BSA by carbodiimide condensation (14). Renal angiotensins were determined with slight modifications of the method described by Fox et al. (6). Briefly, the dried residue was dissolved in a phosphate buffer containing 267 mg/l BSA. Renal angiotensins were extracted by reversible adsorption to phenylsilyl-silica (Bondelut-PH) and quantified by RIA with rabbit anti-ANG I and anti-ANG II sera. Results are reported in femtomoles per milliliter of plasma or in femtomoles per gram of tissue weight.

We verified that blood contamination did not contribute to our measurements of renal RAS components. For this purpose, we compared renal cortex and medulla RAS (RA, ACE activity, ANG I and ANG II levels) of rats whose kidneys were rinsed with physiological serum or not (data not shown). Renal cortex and medulla were dissected in the same conditions as described in Plasma and Kidney Sampling. The results showed that there was no difference between cortex and medulla of kidneys rinsed or not for all the measured components of the RAS. Thus blood contamination does not seem to play a significant part in the renal RAS.

Statistical Analysis

Data are means ± SE. For each parameter, control and treated groups were compared with a one-way ANOVA followed by Tukey's multiple-comparison test (Sigma Stat, SPSS, Chicago, IL). Differences were considered statistically significant at P < 0.05 levels.


    RESULTS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of Salt Depletion by LS Diet and Losartan Treatment on Different Components of the RAS in Plasma

Basal values of the different components of NS rats in plasma are reported in Table 1. Compared with NS rats, salt restriction led to a threefold increase in PRA (P < 0.01) associated with an increase in plasma ANG I (P < 0.001) and ANG II levels (P < 0.05) (Fig. 1). Plasma angiotensinogen levels, ACE activity, and the ANG II-to-ANG I ratio were not affected by salt restriction. In NS+Los rats, the administration of losartan decreased plasma angiotensinogen levels to 10% of the value of NS rats (P < 0.001) whereas it increased PRA (7-fold; P < 0.001), plasma ANG I (6-fold; P < 0.001), and ANG II levels (5.5-fold; P < 0.001). These effects were much more marked than those observed with the LS diet compared with NS rats. Plasma ACE activity was enhanced by losartan (P < 0.01) compared with NS controls, whereas the ANG II-to-ANG I ratio was not affected. In LS+Los rats, the administration of losartan decreased angiotensinogen levels to 5% of the value of LS rats (P < 0.001) and increased PRA (2.2-fold; P < 0.001), ANG I (2.5-fold; P < 0.001), and ANG II levels (2.2-fold; P < 0.05) compared with LS rats. Losartan did not affect ACE activity or the ANG II-to-ANG I ratio.

                              
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Table 1.   Basal values of different components of RAS of NS rats in plasma, renal cortex, and renal medulla



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Fig. 1.   Plasma components of the renin-angiotensin system of rats receiving a normal-sodium diet (NS; 1% NaCl; n = 7), a low-sodium diet (LS; 0.025% NaCl; n = 7), a normal-sodium diet combined with losartan (NS+Los; n = 7) or a low-sodium diet combined with losartan (LS+Los; n = 7). Values are means ± SE. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. NS rats (ANOVA and Tukey's test); dagger P < 0.05 and dagger dagger dagger P < 0.001 vs. LS rats (ANOVA and Tukey's test); Dagger Dagger P < 0.01 and Dagger Dagger Dagger P < 0.001 vs. NS+Los (ANOVA and Tukey's test).

Effects of Salt Depletion by LS Diet and Losartan Treatment on Different Components of RAS in the Renal Cortex

Basal values of the different components of NS rats in the renal cortex are reported in Table 1. In the renal cortex, salt restriction decreased angiotensinogen levels to 50% of the value of NS rats (P < 0.001) and increased RA (1.8-fold; P < 0.05), ANG I levels (1.2-fold; P < 0.001), ANG II levels (2-fold; P < 0.001), and the ANG II-to-ANG I ratio (P < 0.05) compared with NS rats (Fig. 2). In LS rats, ACE activity was not different from that of NS controls. In NS+Los rats, losartan treatment decreased angiotensinogen levels to 45% of the value in NS rats (P < 0.001) and led to an increase in RA (2.7-fold; P < 0.001) compared with NS controls. In contrast to plasma, losartan administration reduced cortical ANG I levels to 50% (P < 0.001) and ANG II levels to 40% (P < 0.001) of NS rats. Losartan enhanced ACE activity (P < 0.05) but did not affect the ANG II-to-ANG I ratio. In LS+Los rats, losartan administration increased RA (1.4-fold; P < 0.001) and markedly reduced ANG I levels to 40% (P < 0.001) and ANG II levels to 10% (P < 0.001) of LS rats. ACE activity was raised by losartan treatment (2.3-fold; P < 0.01), whereas the ANG II-to-ANG I ratio was decreased to 25% of the value in LS rats (P < 0.001). Addition of losartan to LS rats did not affect angiotensinogen levels.


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Fig. 2.   Components of the renin-angiotensin system in the renal cortex of NS (1% NaCl; n = 7), LS (0.025% NaCl; n = 7), NS+Los (n = 7), and LS+Los (n = 7) rats. Values are means ± SE. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. NS rats (ANOVA and Tukey's test); dagger P < 0.05, dagger dagger P < 0.01, and dagger dagger dagger P < 0.001 vs. LS rats (ANOVA and Tukey's test); Dagger Dagger P < 0.01 and Dagger Dagger Dagger P < 0.001 vs. NS+Los (ANOVA and Tukey's test).

Effects of Salt Depletion by LS Diet and Losartan Treatment on Different Components of RAS in the Renal Medulla

Basal values of the different components of NS rats in the renal medulla are reported in Table 1. The LS diet led to a significant increase in ANG I and ANG II levels in the renal medulla compared with NS rats (Fig. 3). Angiotensinogen levels, RA, ACE activity, and the ANG II-to-ANG I ratio were not affected by salt restriction. In NS+Los rats, losartan treatment increased RA (2.3-fold; P < 0.05) but decreased ANG II levels to 40% of the value of NS controls (P < 0.01). Losartan did not modify angiotensinogen levels, ACE activity, or the ratio of ANG II to ANG I. In LS+Los rats, losartan administration reduced ANG I levels to 50% (P < 0.001) and ANG II levels to 25% (P < 0.001) of LS rats. Addition of losartan to LS rats also decreased the ANG II-to-ANG I ratio to 50% of the value in LS rats (P < 0.05) but did not modify angiotensinogen levels or ACE activity.


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Fig. 3.   Components of the renin-angiotensin system in the renal medulla of NS (1% NaCl; n = 7), LS (0.025% NaCl; n = 7), NS+Los (n = 7), and LS+Los (n = 7) rats. Values are means ± SE. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. NS rats (ANOVA and Tukey's test); dagger P < 0.05 and dagger dagger dagger P < 0.001 vs. LS rats (ANOVA and Tukey's test); Dagger P < 0.05 vs. NS+Los (ANOVA and Tukey's test).


    DISCUSSION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The purpose of the present study was to investigate the involvement of AT1 receptors in the renal uptake of ANG II in rats receiving a strict low-salt diet. Our study extends our previous findings (11a) and demonstrates that the increase in renal ANG II induced by 10 days of low-salt intake is reversed to a decrease by 8 days of losartan treatment. The results demonstrate that a significant part of intrarenal ANG II results from an uptake of ANG II mediated via AT1 receptors.

Consistent with previous findings with sodium restriction (11a), we observed a pronounced stimulation of both circulating and renal RAS. As expected, the low-salt diet induced an elevation in PRA associated with an increase in ANG I and ANG II levels in plasma as well as in the renal cortex and medulla. However, the degree of stimulation we observed was less than the one we observed previously. This is likely explained by the duration of salt restriction. In the present study, the rats were treated over 10 days compared with 21 days as in our previous study (11a).

Administration of losartan markedly increased PRA in the NS group as well as in the LS rats; the degree of stimulation exerted by the AT1 blocker losartan was much more than that induced by the low-salt diet. These results are consistent with a major feedback role of ANG II on renin gene expression via AT1 receptors (19). Plasma angiotensinogen levels were depleted by losartan, which can be explained by higher consumption of substrate by the elevated circulating RA and/or blockade of the stimulatory feedback control of ANG II on hepatic angiotensinogen gene expression and secretion (16). Circulating angiotensin levels were increased more by losartan treatment than by sodium restriction, which appears to be accounted for by the marked elevation in PRA. Furthermore, addition of losartan increased plasma ACE activity in rats fed either a normal-salt or a low-salt diet, which is consistent with previous studies (3, 15), although the plasma ANG II-to-ANG I ratio remained unchanged.

As in the plasma, treatment with losartan significantly increased RA in rats with either normal- or low- salt intake; these findings are consistent with a feedback role of ANG II on renin gene expression (12, 20). Some studies demonstrated that blockade of AT1 receptors markedly elevated renal renin mRNA levels in rats fed normal-salt (12, 16) or low-salt (18) diets, suggesting that ANG II has an important direct inhibitory control on the renin gene expression. Moreover, observations that losartan also increased PRA confirm that ANG II inhibited not only renin gene expression but also renin secretion (18). Losartan treatment diminished renal angiotensinogen levels but to a lesser extent than observed in the plasma. These results are consistent with the positive feedback role of ANG II on angiotensinogen mRNA expression in renal cortex in vivo (19, 20). Moreover, Ingelfinger et al. (10) showed that in a immortalized rat proximal tubular cell line (93-p-1-2), in vitro administration of losartan alone in the absence of ANG II infusions resulted in angiotensinogen mRNA steady-state levels slightly lower than those of controls. These findings support the concept that losartan alone could have an effect on angiotensinogen mRNA and thereby could participate in the diminution of angiotensinogen available for ANG I formation. ANG I levels in kidneys of control rats are higher than those reported in the plasma, probably indicating that renal ANG I levels not only are due to a contamination by plasma ANG I but could result from a local synthesis. In contrast to data reported in the literature (3, 30), we observed that blockade of AT1 receptors decreased renal cortical ANG I levels in both NS+Los and LS+Los rats. ANG I levels in the kidneys failed to increase despite a large increase in renin secretion during AT1 receptor antagonism. We propose that in the situation where RA is very high and ANG I levels are decreased, angiotensinogen could become a limiting factor for ANG I formation.

In contrast to the markedly elevated plasma ANG II levels, cortical ANG II levels were diminished by losartan to ~40% of the value in NS rats. The decrease in intrarenal ANG II levels may be the result of the reduction of intrarenal ANG I levels available. However, because ANG II levels decreased significantly more than ANG I levels, we suggest that our data confirm the existence of an uptake of ANG II via AT1 receptors. Nevertheless, in this model, the uptake phenomenon probably does not account for renal ANG II levels as large as described previously after ANG II infusion (29). Administration of losartan to rats fed a low-salt diet caused a 90% fall in intrarenal ANG II levels, whereas ANG I levels remained comparable to the values observed in NS+Los rats compared with the values in LS rats. The finding that losartan blocks the increase in intrarenal ANG II levels after salt restriction shows that intrarenal ANG II augmentation is due, in significant part, to AT1 receptor-mediated binding and internalization of ANG II. The ratio of ANG II to ANG I is of particular relevance and supports the results described above. During salt restriction, the ratio increased, the augmentation of ANG II levels being more marked than that of ANG I levels, whereas during both salt restriction and losartan administration, the ratio decreased because of the pronounced reduction of intrarenal ANG II levels. Wang et al. (24) reported that rats treated with losartan and a low-salt diet manifested enhanced renal AT1A mRNA expression. This upregulation of AT1A mRNA expression could perhaps explain why uptake plays a larger role in rats treated by losartan and a low-salt diet than in those receiving losartan alone. Previous studies using the ANG II-induced hypertension model showed that a significant part of intrarenal ANG II results from the uptake of circulating ANG II via AT1 receptors after ANG II infusion (3, 28-30), but we cannot exclude that the uptake phenomenon also occurs with interstitial ANG II.

In the renal medulla, similar patterns were observed for all the components of the RAS in response to the different treatments. It is interesting to note that the increase of ANG II levels was less important in the medulla compared with the cortex, suggesting that the uptake phenomenon was less active in the medulla despite the high density of AT1 receptors described in this tissue, especially in renal medullary interstitial cells (26, 27). These findings may suggest that the receptors located on these cells are not involved in the uptake phenomenon. The role of the abundant AT1 receptors in the renal medulla remains to be elucidated.

The multiple intrarenal effects of ANG II on both tubular and vascular structures are synergistic and provide a powerful influence on sodium excretion and the pressure-natriuresis relationship. It is likely that elevated intrarenal ANG II levels observed during sodium restriction could contribute to minimize renal fluid and sodium losses and decreased arterial blood pressure in the case of salt deficiency. It also appears that some of the internalized ANG II is protected from degradation (30) and could therefore have intracellular functions. Moreover, recent findings demonstrate that ANG II is either formed or trafficked through intracellular endosomal compartments (9).

In conclusion, we have shown that the augmentation of intrarenal ANG II occurring in rats exposed to a highly sodium-deficient diet is partly due to an uptake of ANG II mediated by AT1 receptors in both the renal cortex and medulla. We obtained no clear evidence for a differential regulation of ANG II levels between these two compartments. Nevertheless, it is interesting to note that in renal tissues the use of ACE inhibitors or AT1 receptor antagonists can lead to a decrease in intrarenal ANG II levels. Uptake occurring at AT1 receptor sites indicates that selective AT1 receptor antagonists may be uniquely effective in preventing this phenomenon.


    FOOTNOTES

Address for reprint requests and other correspondence: M. Grima, Institut de Pharmacologie, Faculté de Médecine, 11, rue Humann, 67085 Strasbourg Cedex, France (E-mail: Michele.Grima{at}pharmaco-ulp.u-strasbg.fr).

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.

July 2, 2002;10.1152/ajprenal.00322.2001

Received 26 October 2001; accepted in final form 28 June 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Alhenc-Gelas, F, Baussant T, Hubert C, Soubrier F, and Corvol P. The angiotensin converting enzyme in the kidney. J Hypertens 7: S9-S14, 1989.

2.   Braam, B, Mitchell KD, Fox J, and Navar LG. Proximal tubular secretion of angiotensin II in rats. Am J Physiol Renal Fluid Electrolyte Physiol 264: F891-F898, 1993[Abstract/Free Full Text].

3.   Campbell, DJ, Kladis A, and Valentijn AJ. Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. J Cardiovasc Pharmacol 26: 233-240, 1995[ISI][Medline].

4.   Campbell, DJ, Lawrence AC, Towrie A, Kladis A, and Valentijn AJ. Differential regulation of angiotensin peptide levels in plasma and kidney of the rat. Hypertension 18: 763-773, 1991[Abstract].

5.   Darby, IA, Congiu M, Fernley RT, Sernia C, and Coghlan JP. Cellular and ultrastructural location of angiotensinogen in rat and sheep kidney. Kidney Int 46: 1557-1560, 1994[ISI][Medline].

6.   Fox, J, Guan S, Hymel AA, and Navar LG. Dietary Na and ACE inhibition effects on renal tissue angiotensin I and II and ACE activity in rats. Am J Physiol Renal Fluid Electrolyte Physiol 262: F902-F909, 1992[Abstract/Free Full Text].

7.   Grima, M, Ingert C, Michel B, Barthelmebs M, and Imbs JL. Renal tissue angiotensins during converting enzyme inhibition in the spontaneously hypertensive rat. Clin Exp Hypertens 19: 671-685, 1997[ISI][Medline].

8.   Ikemoto, F, Song GB, Tominaga M, Kanayama Y, and Yamamoto K. Angiotensin converting enzyme predominates in the inner cortex and medulla of the rat kidney. Biochem Biophys Res Commun 144: 915-921, 1987[ISI][Medline].

9.   Imig, JD, Navar GL, Zou LX, O'Reilly KC, Allen PL, Kaysen JH, Hammond TG, and Navar LG. Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors. Am J Physiol Renal Physiol 277: F303-F311, 1999[Abstract/Free Full Text].

10.   Ingelfinger, JR, Jung F, Diamant D, Haveran L, Lee E, Brem A, and Tang SS. Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine ANG II feedback. Am J Physiol Renal Physiol 276: F218-F227, 1999[Abstract/Free Full Text].

11.   Ingelfinger, JR, Zuo WM, Fon EA, Ellison KE, and Dzau VJ. In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system. J Clin Invest 85: 417-423, 1990[ISI][Medline].

11a.   Ingert, C, Grima M, Coquard C, Barthelmebs M, and Imbs J-L. Effects of dietary salt changes on renal renin-angiotensin system in rats. Am J Physiol Renal Physiol 283: F995-F1002, 2002[Abstract/Free Full Text].

12.   Johns, DW, Peach MJ, Gomez RA, Inagami T, and Carey RM. Angiotensin II regulates renin gene expression. Am J Physiol Renal Fluid Electrolyte Physiol 259: F882-F887, 1990[Abstract/Free Full Text].

13.   Jover, B, Saladini D, Nafrialdi N, Dupont M, and Mimran A. Effect of losartan and enalapril on renal adaptation to sodium restriction in rat. Am J Physiol Renal Fluid Electrolyte Physiol 267: F281-F288, 1994[Abstract/Free Full Text].

14.   Menard, J, and Catt KJ. Measurement of renin activity, concentration and substrate in rat plasma by radioimmunoassay of angiotensin I. Endocrinology 90: 422-430, 1972[ISI][Medline].

15.   Metsarinne, KP, Helin KH, Saijonmaa O, Stewen P, Sirvio ML, and Fyhrquist FY. Tissue-specific regulation of angiotensin-converting enzyme by angiotensin II and losartan in the rat. Blood Press 5: 363-370, 1996[Medline].

16.   Nakamura, A, Iwao H, Fukui K, Kimura S, Tamaki T, Nakanishi S, and Abe Y. Regulation of liver angiotensinogen and kidney renin mRNA levels by angiotensin II. Am J Physiol Endocrinol Metab 258: E1-E6, 1990[Abstract/Free Full Text].

17.   Nussberger, J, Brunner DB, Waeber B, and Brunner HR. Specific measurement of angiotensin metabolites and in vitro generated angiotensin II in plasma. Hypertension 8: 476-482, 1986[Abstract].

18.   Schricker, K, Holmer S, Kramer BK, Riegger GA, and Kurtz A. The role of angiotensin II in the feedback control of renin gene expression. Pflügers Arch 434: 166-172, 1997[ISI][Medline].

19.   Schunkert, H, Ingelfinger JR, and Dzau VJ. Evolving concepts of the intrarenal renin-angiotensin system in health and disease: contributions of molecular biology. Renal Physiol Biochem 14: 146-154, 1991[ISI][Medline].

20.   Schunkert, H, Ingelfinger JR, Jacob H, Jackson B, Bouyounes B, and Dzau VJ. Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II. Am J Physiol Endocrinol Metab 263: E863-E869, 1992.

21.   Seikaly, MG, Arant BS, Jr, and Seney FD, Jr. Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest 86: 1352-1357, 1990[ISI][Medline].

22.   Taugner, R, Buhrle CP, Ganten D, Hackenthal E, Hardegg C, Hardegg G, and Nobiling R. Immunohistochemistry of the renin-angiotensin-system in the kidney. Clin Exp Hypertens A 5: 1163-1177, 1983[ISI][Medline].

23.   Unger, T, Schull B, Rascher W, Lang RE, and Ganten D. Selective activation of the converting enzyme inhibitor MK 421 and comparison of its active diacid form with captopril in different tissues of the rat. Biochem Pharmacol 31: 3063-3070, 1982[ISI][Medline].

24.   Wang, DH, Du Y, Zhao H, Granger JP, Speth RC, and Dipette DJ. Regulation of angiotensin type 1 receptor and its gene expression: role in renal growth. J Am Soc Nephrol 8: 193-198, 1997[Abstract].

25.   Welsch, C, Grima M, Giesen EM, Helwig JJ, Barthelmebs M, Coquard C, and Imbs JL. Assay of tissue angiotensin converting enzyme. J Cardiovasc Pharmacol 14: S26-S31, 1989[ISI][Medline].

26.   Zhuo, J, Maric C, Harris PJ, Alcorn D, and Mendelsohn FA. Localization and functional properties of angiotensin II AT1 receptors in the kidney: focus on renomedullary interstitial cells. Hypertens Res 20: 233-250, 1997[Medline].

27.   Zhuo, J, Moeller I, Jenkins T, Chai SY, Allen AM, Ohishi M, and Mendelsohn FA. Mapping tissue angiotensin-converting enzyme and angiotensin AT1, AT2 and AT4 receptors. J Hypertens 16: 2027-2037, 1998[ISI][Medline].

28.   Zou, LX, Hymel A, Imig JD, and Navar LG. Renal accumulation of circulating angiotensin II in angiotensin II-infused rats. Hypertension 27: 658-662, 1996[Abstract/Free Full Text].

29.   Zou, LX, Imig JD, Hymel A, and Navar LG. Renal uptake of circulating angiotensin II in Val5-angiotensin II-infused rats is mediated by AT1 receptor. Am J Hypertens 11: 570-578, 1998[ISI][Medline].

30.   Zou, LX, Imig JD, Von Thun AM, Hymel A, Ono H, and Navar LG. Receptor-mediated intrarenal angiotensin II augmentation in angiotensin II-infused rats. Hypertension 28: 669-677, 1996[Abstract/Free Full Text].


Am J Physiol Renal Fluid Electrolyte Physiol 283(5):F1003-F1010
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