(Hypertension. 1997;30:563.)
© 1997 American Heart Association, Inc.
Articles |
Opposite Feedback Control of Renin and Aldosterone Biosynthesis in the Adrenal Cortex by Angiotensin II AT1-Subtype Receptors
From the Department of Internal Medicine "Federico II" University Naples (B.G., R.R., C.S., A.N., O.P.), the IRCCS Istituto Neurologico Mediterraneo "Neuromed" Pozzilli (Is) (S.R., A.P., I.E., P. De P., M.V.), and the Department of Experimental Medicine and Pathology "La Sapienza University" (M.V.), Rome, Italy.
Correspondence to Massimo Volpe, MD, Istituto Neurologico Mediterraneo "Neuromed," Via Atinense 18, Località Camerelle, 86077 Pozzilli (Is), Italy. E-mail volpema{at}cds.unina.it
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Abstract |
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Abstract The aims of this study were to identify whether tissue renin is regulated by a negative-feedback mechanism produced by locally generated angiotensin (Ang II) in the adrenal cortex and to detect the pathway of Ang II modulation. For this purpose, in 36 12-week old, salt-restricted, nephrectomized Sprague-Dawley rats, we studied the effects of the Ang II AT1-subtype receptor antagonist losartan and of the Ang II AT2-subtype receptor antagonist PD123319 on renin mRNA and activity, aldosterone synthase mRNA, and AT1a-, AT1b-, and AT2-subtype receptor expression in the adrenal cortex. Ten additional rats, kept on a regular diet and then nephrectomized, were also studied. In salt-restricted, nephrectomized rats, losartan administration caused increases of adrenal renin mRNA (P<.05) and activity (P<.05) and a concomitant reduction of aldosterone synthase mRNA (P<.05). In addition, after losartan AT1b, receptor mRNA was reduced (P<.05), AT1a receptor mRNA was unchanged, and AT2 mRNA was increased (P<.05). PD123319 did not significantly modify any of these parameters. In conclusion, in salt-restricted, nephrectomized rats, selective antagonism of AT1-subtype receptors stimulates the expression and the activity of renin in the adrenal cortex. This observation demonstrates that Ang II locally formed in the adrenal cortex exerts a modulatory negative-feedback action on adrenal renin biosynthesis independent of the influence of the circulating renin-Ang system; this action is largely mediated through the AT1b-subtype receptors.
Key Words: aldosterone • adrenal • renin • angiotensin II • receptors
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Introduction |
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Local RASs have been described in different tissues and organs.1 2 3 4 The activity of the tissue RASs is modulated by maneuvers and stimuli that commonly also regulate the circulating RAS; such stimuli include nephrectomy,5 sodium and potassium balance,6 7 and Ang II.8 In addition, the functions of the local RAS have been demonstrated or postulated in various tissues.9 10 11 12 13 However, investigation of the regulation and function of tissue RASs has been difficult to interpret because of the confounding action of concomitant changes in the circulating RAS of renal origin. In particular, intrinsic regulation of the renin-Ang cascade within the tissues cannot be dissected from the influence of the endocrine system, and the available data are mostly derived from in vitro studies.8 14 Bilateral nephrectomy may provide an effective model to study regulation and function of local tissue RASs in the absence of the circulating system. In fact, 48 hours after bilateral nephrectomy, plasma renin activity falls below the level of detection.15
In the present study, we used this experimental approach to investigate the feedback mechanisms that regulate the tissue RAS within the adrenal cortex. All the components of the RAS have been described in the adrenal cortex,16 and its function has been linked to the regulation of mineralocorticoid biosynthesis.17 18 Although in vitro studies suggest that locally generated Ang II may influence the formation of renin in the adrenal tissue,19 20 there is no evidence that such a mechanism is operating in vivo. The aims of the present study were thus to (1) identify whether the adrenal RAS is regulated by an Ang II–mediated negative-feedback mechanism that operates independently of the systemic RAS and (2) detect the intrinsic mechanisms of the autocrine negative modulation of Ang II on renin expression.
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Methods |
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The study was performed in 46 12-week-old male Sprague-Dawley rats weighing 250 to 350 g. The animals were purchased from Morini (Polo D’Enza, Reggio Emilia, Italy).
Experimental Protocol
The protocol was performed according to the guidelines for
animal care and treatment of the European Community and was approved by
the local committee of our institution. After arrival at the
laboratory, the animals were housed under controlled conditions of
light, temperature, and humidity and fed regular rat chow and tap water
ad libitum for 1 week. To enhance the activity of the adrenal RAS as
previously reported from our laboratory,18 21 22 36 rats
were maintained for 1 week on a diet based on low salt intake (NaCl,
0.04%; K+, 0.68%; Laboratori Piccioni). Fifteen animals
on the low-salt regimen remained untreated and 15 rats were
concomitantly treated with the Ang II AT1-subtype receptor
antagonist losartan for 1 week. Losartan
was administered in the drinking water at the dosage of 10 mg ·
kg-1 · d-1. This
dosage has been shown to completely inhibit the Ang II
AT1-subtype–mediated effects on blood pressure and
aldosterone biosynthesis.23 The drug was
kindly provided by Dr R. Smith from DuPont-Merck Pharmaceutical Co
(Wilmington, Del). All rats underwent bilateral nephrectomy during
brief anesthesia obtained by intramuscular injection of a
mixture of ketamine (Ketalar, 160 mg/kg body weight) and
xylazine (Rompun, 10 mg/kg body weight). Care was taken to
preserve the adrenal glands on removal of the kidney. In six
salt-restricted, nephrectomized rats, the effects of the Ang II
AT2-subtype receptor antagonist PD123319,
kindly provided by Dr C.L. Germain from Parke-Davis (Ann Arbor, Mich),
were tested and given at a dosage of 50 µg ·
kg-1 · min-1 for 2 hours. The
drug was given intravenously through a jugular polyethylene
cannula that had been placed during the week of the low-salt diet. This
dosage of PD123319 has been shown to provide selective and complete
inhibition of the Ang II AT2-subtype
receptors.24
Finally, the 10 remaining rats were maintained on a regular diet throughout the study, including the nephrectomy phase, to evaluate the effects of salt restriction.
Measurements
The rats were euthanized by decapitation without premedication
48 hours after bilateral nephrectomy to obtain plasma and tissue for
measurements. Plasma renin activity (ng Ang I per mL per hour) and
adrenal renin activity (ng Ang I per mL per hour per mg tissue protein)
were measured as previously described.18 Sodium and
potassium concentrations in serum were measured by flame
photometry.
RNA Preparation and Northern Blot Analysis
The adrenal capsules were carefully dissected from the rest of
the adrenal gland and immediately frozen in liquid N2 and
kept at -70°C until RNA extraction. Total RNA was extracted from one
individual adrenal capsule from each animal by the guanidinium
thiocyanate–phenol-chloroform method.25 For Northern
blotting, total RNA (15 µg per lane) was electrophoresed on 1%
agarose gel containing 2.2 mol/L formaldehyde and transferred to
Hybond-N filters (Amersham).
Prehybridization and hybridization for the aldosterone
synthase cytochrome P450 were carried out at 50°C in a buffer
containing 5x SSC, 20 mmol/L
NaH2PO4 (pH 7.3), 3.5% SDS, 10x Denhardt’s
solution, 10% dextran sulfate, and 0.2 mg/mL denatured salmon
sperm DNA, with the specific oligonucleotide
corresponding to positions 857-891 of rat aldosterone
synthase cDNA labeled with [
-32P]dATP using the
polynucleotide kinase (New England Biolabs).
To avoid cross-hybridization with the isoenzyme 11ß-hydroxylase, an excess of the unlabeled oligonucleotide corresponding to positions 863-882 of the rat 11ß-hydroxylase cDNA was added to the hybridization mixture.26 The two oligonucleotides were manufactured by GENSET (Paris, France). Washings were performed in 2x SSC and 1% SDS at room temperature and in 0.1x SSC and 0.1% SDS at 42°C. Prehybridizations (2 hours) and hybridizations with the rat Ang II AT1a-, AT1b-, and AT2-subtype receptors (kindly provided by Dr K. Lindpaintner, Harvard Medical School, Boston, Mass) and GAPDH cDNAs were carried out in a mixture containing 50% formamide, 5xSSC, 50 mmol/L Na2HPO4 (pH 7.3), 5x Denhardt’s solution, 0.1% SDS, and 0.25 mg/mL salmon sperm DNA at 42°C for 16 hours. Washings were performed in 2xSSC and 1% SDS at room temperature followed by a stringent washing at 50°C in 0.2xSSC and 0.1% SDS. Filters were exposed for 24 to 72 hours to preflashed Kodak X-AR5 film at -80°C with intensifying screens. The autoradiographic bands were analyzed by densitometric scanning and normalized by GAPDH levels. Data are expressed as mean±SEM of the values obtained in three independent experiments.
cDNA Synthesis and rt-PCR
To avoid contamination of RNA with genomic DNA, the samples were
treated with DNase-RNase free for 15 minutes at 37°C and then
inactivated at 94°C for 5 minutes.
Single-strand cDNA synthesis was performed on 1 µg of total RNA. The
reaction was carried out in 20 µL of reaction buffer (50
mmol/L Tris-HCl, pH 8.3; 75 mmol/L KCl; 15
mmol/L MgCl2; 10 mmol/L DTT; 500
µmol/L dNTPs) containing 20 pmol of random primers
(Boehringer Mannheim) and 200 U of reverse transcriptase
(Superscript TM, GIBCO BRL). The reaction was stopped by adding 5 µL
EDTA (0.5 mol/L), and a final volume of 50 µL was achieved
with sterile water. To verify the absence of genomic DNA contamination
of RNA, an aliquot (
100 ng) of each sample was subjected to PCR
amplification without the reverse-transcriptase step.
Five microliters of cDNA overlaid with mineral oil was amplified in 70 µL reaction buffer containing 10 mmol/L Tris-HCl, pH 8.3; 50 mmol/L KCl; 1.5 mmol/L MgCl2; 200 µmol/L dNTPs; and 20 pmol of each oligonucleotide primer, and 1 U Taq DNA polymerase (Boehringer Mannheim) was added. The thermal profile used on a Perkin Elmer-Cetus thermal cycler consisted of 97°C for 5 minutes followed by 29 cycles, the first five of which consisted of 1-minute denaturation at 94°C, 1-minute annealing at 60°C, and 1-minute extension at 72°C; the remaining 24 cycles consisted of 50 seconds at 94°C, 50 seconds at 55°C, and 45 seconds at 72°C. The final extension was carried out for 10 minutes. In preliminary studies, we found that the amplification reaction reached a plateau after 22 cycles for GAPDH and 29 cycles for renin; therefore, GAPDH primers were added after the first seven cycles. Under these conditions the reaction is linearly related to the initial cDNA concentration (data not shown). Semiquantitative rt-PCR was performed by coamplifying renin and GAPDH. Aliquots (10 µL) of the rt-PCR products were taken up at 26 and 29 cycles, loaded twice on 1% agarose gels with TBE buffer, and blotted on N-Hybond filters (Amersham). After Southern blotting the filter was cut into two parts, each containing all the rt-PCR products. The two filters were then hybridized, one with renin cDNA (kindly provided by Dr K.R. Lynch, University of Virginia Medical School, Charlottesville, Va) and the other with GAPDH cDNA in a mixture containing 7% SDS, 0.5 mol/L Na2HPO4, and 1 mmol/L EDTA; washed twice in 25 mmol/L Na2HPO4 and 1% SDS at room temperature and once at 65°C; and exposed to preflashed Kodak X-AR5 films at -70°C using intensifying screens. The autoradiographic bands were analyzed by densitometric scanning and normalized to GAPDH levels.
The renin/GAPDH ratio was measured throughout the experiment to test the linearity of the reaction, and all the samples in which the renin/GAPDH ratio was not constant between cycles 26 and 29 of the amplification reaction were dropped out. All the experiments were performed three times in duplicate, and the interassay variability in these conditions was <10%.
Choice of Primers
For the renin gene, two oligonucleotide primers
were chosen on the cDNA sequence. The first is located at
nucleotide 819 (5'-GATGGAGTCATCCCTGTCTTCG-3') and the
second at nucleotide 1262 (5'-GTCATCGTTCCTGAAGGGATTC-3'),
thus amplifying a cDNA fragment of 464 bp. The GAPDH
oligonucleotide primers are located at
nucleotides 369 (5'-TTCACCACCACCATGGAGAAGGCT-3') and 715
(5'-ACAGCCTTGGCAGCACCAGT-3' on GAPDH cDNA, thus amplifying a 346-bp
fragment.
Statistical Analysis
Data are expressed as mean+SEM. Multiple comparison
analysis was performed by two-way ANOVA by factoring by group
and treatment; a nonparametric post hoc test
(Kruskal-Wallis) was used to detect significance among the different
experimental conditions.
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Results |
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Plasma renin activity was undetectable in the group of nephrectomized rats maintained on a regular diet and was 0.13±0.1 ng Ang I per mL per hour in the salt-restricted nephrectomized rats. Serum potassium concentrations (mmol/L) were elevated in all groups of rats as a consequence of nephrectomy. However, no significant difference could be observed among the treatment groups (7.3±2.3 in nephrectomized rats on a regular diet; 7.7±2.5 in salt-restricted nephrectomized rats; 7.5±2.5 in losartan-treated, salt-restricted, nephrectomized rats; 7.6±2.0 in PD123319-treated, salt-restricted nephrectomized rats).
Adrenal renin activity was 227±96 ng Ang I per mL per hour per mg tissue protein in the rats on a regular diet and 298±73 in the salt-restricted group (P<.05). Also renin mRNA (+193±10%, P<.05) and aldosterone synthase mRNA (+130±13%, P<.05) were increased in the adrenal cortex of the salt-restricted group compared with the group of rats kept on a regular diet.
Fig 1 shows the effects of losartan and PD123319 on renin and aldosterone synthase mRNAs in the adrenal cortex in salt-restricted, nephrectomized rats. Losartan caused opposite effects on renin and aldosterone synthase mRNAs. In fact, renin mRNA increased by 156±15% (P<.05), but aldosterone synthase mRNA decreased by 384±45% (P<.05). In contrast, PD123319 did not significantly affect either renin mRNA or aldosterone synthase mRNA in the adrenal cortex. Also, adrenal renin activity was stimulated by losartan (369±92 ng Ang I per mL per hour per mg tissue protein, P<.05), whereas it was not affected by PD123319.
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AT1a-subtype receptor mRNA was barely detectable in the adrenal cortex of nephrectomized rats kept on a regular diet. Salt restriction tended to stimulate the expression of AT1a-subtype receptors, although the increment (+127±25%) did not achieve statistical significance. Losartan treatment did not further modify AT1a mRNA (104±12% of the value obtained in the salt-restricted, nephrectomized rats). Similarly, PD123319 did not influence the expression of the AT1a isoform in the adrenal cortex.
AT1b-subtype receptor mRNA in the adrenal cortex was increased by salt restriction in the nephrectomized rats (P<.05), whereas adrenal AT2-subtype receptor mRNA was decreased (P<.05). As shown in Fig 2, losartan caused a marked reduction of adrenal AT1b-subtype receptor mRNA (P<.05) and an increase in adrenal AT2-subtype receptor mRNA (P<.05) in the salt-restricted, nephrectomized rats. Treatment with PD123319 did not significantly modify either AT1b- or AT2-subtype receptor mRNA in the adrenal cortex of these animals.
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Discussion |
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In the present study we have shown that in bilaterally nephrectomized rats, ie, independently of any influence of the circulating RAS of renal origin, the selective antagonism of Ang II AT1-subtype receptors by losartan produces a significant stimulation of renin mRNA and activity in the adrenal cortex. This finding indicates that Ang II locally formed in the adrenal capsules exerts a modulatory negative-feedback action on adrenal renin expression and biosynthesis. The administration of losartan simultaneously caused a selective significant reduction of the expression of the AT1b isoform of the Ang II AT1-subtype receptors and an inhibition of aldosterone synthase expression, which is largely modulated by the action of adrenal Ang II on AT1b-subtype receptors.8 9 18 27 These observations suggest that the autocrine opposite effects of Ang II on renin and aldosterone biosynthesis in the adrenal cortex are largely mediated through the Ang II AT1b-subtype receptors. A predominant role of the AT1b-subtype receptors in the adrenal cortex and in the regulation of aldosterone biosynthesis has been indeed already shown,27 28 29 whereas AT1a-subtype receptor expression and functional roles appear to be more important in other tissues, such as smooth muscle cells, lung, liver, and largely in the kidney.29 30 Finally, our observation that antagonism of the Ang II AT2-subtype receptors by PD123319 did not affect renin expression and activity as well as Ang II receptors and aldosterone synthase mRNA confirms and extends previous observations from our laboratory showing that in the adrenal cortex, Ang II regulates renin and aldosterone biosynthesis through the selective stimulation of the AT1-subtype receptors.18 22
The present data are the first demonstration of the mechanisms underlying the autocrine negative-feedback control of renin activity in the adrenal cortex. In fact, previous in vitro studies have only suggested that Ang II may influence renin in the adrenal tissue.19 20 In addition, in a study by Baba et al5 a reduction of adrenal capsular renin activity observed during Ang II infusion in nephrectomized rats was reported. However, the use of an exogenous infusion of Ang II at the dosage of 200 ng/min in anesthetized rats did not permit those authors to demonstrate the existence of a physiological feedback mechanism on adrenal renin.
The circulating RAS exerts a major influence on the activity of local tissue RASs. In particular, maneuvers or stimuli that modify plasma renin activity, such as salt depletion,22 potassium,31 Ang II infusion,32 and nephrectomy,5 also induce large modifications in the activity of the adrenal system. This makes difficult analysis of the intrinsic mechanisms that regulate the tissue RAS within the adrenal gland. Our experimental model based on the study of responses to Ang II antagonists 48 hours after bilateral nephrectomy provides an effective approach to investigate the tissue regulatory pathways of the RAS in the adrenal cortex, without the concomitant influence of the circulating RAS. Other potential confounding factors, such as changes in sodium intake or potassium levels, could be ruled out because the study was performed in sodium-restricted rats that also displayed a uniform degree of hyperkalemia secondary to removal of the kidneys. In fact, investigation of the autocrine regulatory mechanism of the local RAS provides important insights for a more complete understanding of the physiological role of Ang II as well as of the pharmacological actions of Ang II antagonists. In this latter regard, our findings obtained in the adrenal cortex show that expression of Ang II receptors is modified by salt restriction and by losartan in nephrectomized rats and that the AT1- and AT2-subtype receptors show opposite behavior in response to these maneuvers. In particular, we observed that salt restriction stimulated AT1-subtype receptor expression in this model, with a concomitant reduction of AT2-subtype receptors.
Losartan treatment, in contrast, selectively reduced expression of the AT1b-subtype receptor while AT1a-subtype receptors were not affected, and expression of AT2-subtype receptors in the adrenal cortex was stimulated. This latter response was most likely the consequence of the Ang II excess in the adrenal cortex as a result of the blockade of AT1-subtype receptors. An alternative possibility that should be taken into account is that intracellular signaling linked to the stimulation or inhibition of the AT1-subtype receptors may regulate expression of the AT2-subtype receptors. Our study, however, does not permit us to define whether this "cross-talk" of Ang receptors in adrenal cortex tissue is merely a consequence of the changes in Ang II concentrations because we did not measure levels of the octapeptide. The possibility that the modified expression of AT2-subtype receptors after losartan plays a role in the stimulation of renin or in the suppression of aldosterone synthase mRNA is not supported by our findings. In fact, the lack of influence of the treatment with the Ang II AT2-subtype receptor antagonist PD123319 does not suggest a direct role for these receptors in the opposite feedback control exerted by adrenal Ang II on renin and mineralocorticoid biosynthesis. This, in contrast, is inhibited by losartan, and thus it appears to be largely mediated by the Ang II AT1-subtype receptors.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors wish to thank Dr Assunta Nappo for her technical assistance.
Received March 17, 1997; first decision April 21, 1997; accepted May 13, 1997.
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References |
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