Adrenal Renin Research Articles

Dysregulation of Aldosterone Secretion in Mast Cell-Deficient Mice.

Resident adrenal mast cells have been shown to activate aldosterone secretion in rat and man. Especially, mast cell proliferation has been observed in adrenal tissues from patients with aldosterone-producing adrenocortical adenoma. In the present study, we show that the activity of adrenal mast cells is stimulated by low-sodium diet and correlates with aldosterone synthesis in C57BL/6 and BALB/c mice. We have also investigated the regulation of aldosterone secretion in mast cell-deficient C57BL/6 KitW-sh/W-sh mice in comparison with wild-type C57BL/6 mice. KitW-sh/W-sh mice submitted to normal sodium diet had basal plasma aldosterone levels similar to those observed in wild-type animals. Conversely, low-sodium diet unexpectedly induced an exaggerated aldosterone response, which seemed to result from an increase in adrenal renin and angiotensin type 1 receptor expression. Severe hyperaldosteronism was associated with an increase in systolic blood pressure and marked hypokalemia, which favored polyuria. Adrenal renin and angiotensin type 1 receptor overexpression may represent a compensatory mechanism aimed at activating aldosterone production in the absence of mast cells. Finally, C57BL/6 KitW-sh/W-sh mice represent an unexpected animal model of primary aldosteronism, which has the particularity to be triggered by sodium restriction.

Renin knockout rat: control of adrenal aldosterone and corticosterone synthesis in vitro and adrenal gene expression.

The classic renin-angiotensin system is partly responsible for controlling aldosterone secretion from the adrenal cortex via the peptide angiotensin II (ANG II). In addition, there is a local adrenocortical renin-angiotensin system that may be involved in the control of aldosterone synthesis in the zona glomerulosa (ZG). To characterize the long-term control of adrenal steroidogenesis, we utilized adrenal glands from renin knockout (KO) rats and compared steroidogenesis in vitro and steroidogenic enzyme expression to wild-type (WT) controls (Dahl S rat). Adrenal capsules (ZG; aldosterone production) and subcapsules [zona reticularis/fasciculata (ZFR); corticosterone production] were separately dispersed and studied in vitro. Plasma renin activity and ANG II concentrations were extremely low in the KO rats. Basal and cAMP-stimulated aldosterone production was significantly reduced in renin KO ZG cells, whereas corticosterone production was not different between WT and KO ZFR cells. As expected, adrenal renin mRNA expression was lower in the renin KO compared with the WT rat. Real-time PCR and immunohistochemical analysis showed a significant decrease in P450aldo (Cyp11b2) mRNA and protein expression in the ZG from the renin KO rat. The reduction in aldosterone synthesis in the ZG of the renin KO adrenal seems to be accounted for by a specific decrease in P450aldo and may be due to the absence of chronic stimulation of the ZG by circulating ANG II or to a reduction in locally released ANG II within the adrenal gland.

Severe Hyperaldosteronism in Neonatal Task3 Potassium Channel Knockout Mice Is Associated With Activation of the Intraadrenal Renin-Angiotensin System

Task3 K(+) channels are highly expressed in the adrenal cortex and contribute to the angiotensin II and K(+) sensitivity of aldosterone-producing glomerulosa cells. Adult Task3(-/-) mice display a partially autonomous aldosterone secretion, subclinical hyperaldosteronism, and salt-sensitive hypertension. Here, we investigated the age dependence of the adrenal phenotype of Task3(-/-) mice. Compared with adults, newborn Task3(-/-) mice displayed a severe adrenal phenotype with strongly increased plasma levels of aldosterone, corticosterone, and progesterone. This adrenocortical dysfunction was accompanied by a modified gene expression profile. The most strongly up-regulated gene was the protease renin. Real-time PCR corroborated the strong increase in adrenal renin expression, and immunofluorescence revealed renin-expressing cells in the zona fasciculata. Together with additional factors, activation of the local adrenal renin system is probably causative for the severely disturbed steroid hormone secretion of neonatal Task3(-/-) mice. The changes in gene expression patterns of neonatal Task3(-/-) mice could also be relevant for other forms of hyperaldosteronism.

Secretory and cytosolic (pro)renin in kidney, heart, and adrenal gland

Renin is commonly known as a secretory glycoprotein, which is expressed, stored, and secreted in a regulated manner by the kidney. The rat kidney exclusively expresses secretory renin. In this organ, renin regulates glomerular filtration rate, vascular resistance, and sodium reabsorbtion. In the adult rat heart, secretory preprorenin is not expressed. Instead, an alternative renin transcript is expressed that encodes for a previously unrecognized cytosolic renin. The expression of cytosolic but not of secretory renin increases markedly after myocardial infarction, indicating a role specifically for cytosolic renin in postischemic repair processes. In the adrenal gland, secretory renin is expressed and provides the basis for an intra-adrenal angiotensin (ANG) II amplification system. This amplification system reduces the demand for circulating ANGII to stimulate aldosterone production and thus minimizes any detrimental effects of circulating ANGII in other tissues. The adrenal gland additionally expresses cytosolic renin, which is targeted to mitochondria. Adrenal cytosolic renin increases aldosterone production plasma renin independently.

Altered regulation of renal interstitial hydrostatic pressure and the renal renin–angiotensin system in the absence of atrial natriuretic peptide

Although it has been well established that atrial natriuretic peptide gene-disrupted (ANP-/-) mice are a useful model of salt-sensitive hypertension, surprisingly little is known about the control of their intrarenal renin-angiotensin system (RAS) and pressure-natriuresis mechanism, key components in blood pressure, fluid and electrolyte regulation. The aim of this study was to determine whether ANP disruption results in changes in the renal and adrenal local RAS and the acute pressure-natriuresis mechanism. Renal and adrenal renin, angiotensin type 1 (AT1)(A and B) and angiotensin type 2 (AT2) receptor messenger RNA expression levels were determined by northern blotting or real time reverse transcriptase-polymerase chain reaction. Plasma aldosterone and renal and adrenal angiotensin II peptide levels were determined by radioimmunoassay. To examine the acute pressure-natriuresis response, changes in renal interstitial hydrostatic pressure (RIHP) were assessed after manipulations of renal arterial pressure (RAP) in anaesthetized mice. Renal and adrenal renin mRNA and angiotensin II levels were lower in ANP-/- and +/- mice compared with +/+mice. ANP-/- mice also had greater renal AT1A and adrenal AT2 mRNA levels compared with the other genotypes. RAP and RIHP were significantly higher in -/-mice compared with +/+mice. Furthermore, there was a blunted slope of the RAP-RIHP relationship after increases in RAP in ANP-/- mice. These data indicate that ANP disruption results in a blunting of the dynamic properties of the acute pressure-natriuresis mechanism at increased levels of RAP, as well as a reduced expression of renal and adrenal local RAS.

Adrenal Aldosterone Biosynthesis Is Elevated in a Model of Chronic Renal Failure – Role of Local Adrenal Renin-Angiotensin System

Background: Aldosterone seems to play a role in the development of chronic renal failure and proteinuria. We investigated the adrenal aldosterone production and the adrenal renin-angiotensin system (RAS) in rats with 5/6 nephrectomy with and without spironolactone treatment. Methods: Sprague-Dawley rats underwent 5/6, 4/6 nephrectomy, heminephrectomy and sham operation. After 1 and 4 weeks creatinine clearance, urinary protein excretion, plasma aldosterone concentration, and plasma renin activity were measured. In adrenals mRNA expression of aldosterone synthase (CYP11B2) and genes of the RAS were measured. Results: Creatinine clearance was significantly decreased and proteinuria significantly elevated in 5/6 nephrectomy. Treatment with spironolactone significantly reduced proteinuria after 8 but not after 30 days. With reduction of renal mass, renal renin mRNA and plasma renin activity were reduced significantly. In early 5/6 nephrectomy plasma aldosterone concentration was increased and in parallel adrenal CYP11B2 mRNA was increased significantly. Both were further augmented by spironolactone. Adrenal renin was up-regulated in 5/6 nephrectomy and further stimulated with spironolactone, possibly serving as a stimulus for the adrenal aldosterone synthesis. Conclusion: In early chronic renal failure after 5/6 nephrectomy adrenal aldosterone production is elevated despite a marked decrease of plasma renin activity. An up-regulated adrenal RAS may contribute to the observed increase in aldosterone.

A Serine Protease Inhibitor, Nafamostat Mesilate, Suppresses Aldosterone Secretions In Vivo

To examine the role of serine proteases in the control of aldosterone (Ald) secretion, we studied the effects of nafamostat mesilate (Naf), a serine protease inhibitor, on in vivo Ald secretion and Ald content in the rat adrenal gland. Either Naf (2 mg/kg/h; n=10) or saline (2 ml/h; n=10) was administered intravenously for 30 min to anesthetized Wistar rats whose left adrenal vein was cannulated selectively via the inferior vena cava. Naf caused a significant decrease in Ald secretion rate compared to saline (1.99+/-0.32 vs. 3.42+/-0.56 ng/min, p <0.001), while adrenal blood flow, mean arterial pressure and plasma renin activity in the adrenal venous blood did not differ between the two groups. In a separate trial, adrenal Ald content, adrenal renin content, plasma adrenocorticotropic hormone (ACTH) and plasma potassium did not differ between rats treated with Naf (n=7) and those administered saline (n=7). These data suggested that Naf-inhibitable serine proteases may participate in the control of Ald secretion through mechanism(s) other than hemodynamic changes, adrenal renin, ACTH, and/or plasma potassium.

Genetic disruption of atrial natriuretic peptide receptor-A alters renin and angiotensin II levels.

We have studied cardiovascular and renal phenotypes in Npr1 (genetic determinant of natriuretic peptide receptor-A; NPRA) gene-disrupted mutant mouse model. The baseline systolic arterial pressure (SAP) in 0-copy mutant (-/-) mice (143 +/- 2 mmHg) was significantly higher than in 2-copy wild-type (+/+) animals (104 +/- 2 mmHg); however, the SAP in 1-copy heterozygotes (+/-) was at an intermediate value (120 +/- 4 mmHg). To determine whether Npr1 gene function affects the renin-angiotensin-aldosterone system (RAAS), we measured the components of RAAS in plasma, kidney, and adrenal gland of 0-copy, 1-copy, and 2-copy male mice. Newborn (2 days after the birth) 0-copy pups showed 2.5-fold higher intrarenal renin contents compared with 2-copy wild-type counterparts (0-copy 72 +/- 12 vs. 2-copy 30 +/- 7 microg ANG I. mg protein(-1). h(-1), respectively). The intrarenal ANG II level in 0-copy pups was also higher than in 2-copy controls (0-copy 33 +/- 5 vs. 2-copy 20 +/- 2 pg/mg protein, respectively). However, both young (3 wk) and adult (16 wk) 0-copy mutant mice showed a dramatic 50-80% reduction in plasma renin concentrations (PRCs) and in expression of renal renin message compared with 2-copy control animals. In contrast, the adrenal renin content and mRNA expression levels were 1.5- to 2-fold higher in 0-copy adult mice than in 2-copy animals. The results suggest that inhibition of renal and systemic RAAS is a compensatory response that prevents greater increases in elevated arterial pressures in adult NPRA null mutant mice. However, the greater renin and ANG II levels seen in 0-copy newborn pups provide evidence that the direct effect of NPRA activation on renin is an inhibitory response.

Renin-angiotensin system in the adrenal.

Extrarenal renin has been found in a number of tissues. All the components of the renin-angiotensin system have been identified in the adrenal cortex. Adrenal renin has been found in many animal species, including the human, but most of the studies have been carried out in the rat. Renin is present and synthesized mainly in the zona glomerulosa cells. Renin production is under physiological control and can be influenced by ACTH, changes in electrolyte balance and the genetic background of the rat. The evidence suggests that adrenal renin plays a role as a local hormone in regulating aldosterone production by the zona glomerulosa cells.

Adrenal renin expression and its role in ren-2 transgenic rats TGR(mREN2)27.

Transgenic rats, termed TGR(mREN2)27, have been generated carrying the mouse ren-2 renin gene. As intended the gene was expressed highly within the adrenal gland offering the opportunity to study the intraadrenal renin-angiotensin system in vivo. Concomitantly with increased adrenal renin activity, the production of adrenocortical steroids are elevated and the regulation of aldosterone production is impaired in TGR(mREN2)27. Furthermore, the transgenic rats develop severe sodium dependent hypertension. Since kidney and plasma renin concentrations and plasma angiotensins are low in the transgenic model, those factors cannot account for the altered regulation of aldosterone production. Instead the experiments with TGR(mREN2)27 demonstrate the functional role of the local adrenal renin-angiotensin system.

Adrenal renin-angiotensin-aldosterone system in streptozotocin-diabetic rats.

Previous studies have indicated that the local renin-angiotensin system (RAS) plays an important role in the regulation of aldosterone release. We focused this study on examining the dissociating changes in circulating RAS and adrenal RAS, and we produced a low plasma renin status in streptozotocin (STZ)-induced diabetic rats. Four and six weeks after treatment with STZ, the rats showed hyperglycemia, hyporeninemia, decrease in plasma angiotensin II (AII), and a slight, but non-significant increase in plasma aldosterone in the rats. The adrenal renin activity and aldosterone concentration were significantly increased in the group of rats six weeks after induction of diabetes compared to those in control rats. The group of rats four weeks after induction of diabetes showed an increase in adrenal aldosterone concentration and a slight, but non-significant increase in adrenal renin activity. Plasma ACTH, serum sodium, and potassium were unchanged in both treatment groups compared to the control. The present results indicate that hyperactivity or residual activity of adrenal RAS under hyporeninemia is associated with severe diabetes mellitus.

Role of tissue renin in the regulation of aldosterone biosynthesis in the adrenal cortex of nephrectomized rats.

The aim of the study was to investigate whether the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in the adrenal gland and to explore the mechanisms of this action. Twelve-week-old male Sprague-Dawley rats were studied: 22 rats were maintained on a regular diet; 27 and 22 rats received a low salt diet with and without treatment, respectively, with the angiotensin II (Ang II) AT1-subtype receptor antagonist losartan (10 mg/kg per day). A fraction of each group of rats underwent bilateral nephrectomy (n = 12, 15, and 10, respectively) and was killed 48 hours later. In an additional group of 24 (12 intact and 12 nephrectomized) rats, the effects of the Ang II AT2-subtype receptor antagonist PD123319 were investigated. In intact rats, plasma renin activity (PRA) and adrenal renin activity and expression were progressively raised by salt restriction and losartan, whereas aldosterone synthase mRNA and plasma aldosterone (PA) levels were increased by salt restriction and reduced by losartan. Forty-eight hours after nephrectomy, PRA fell to undetectable levels; in contrast, adrenal renin expression, assessed by semiquantitative reverse-transcriptase polymerase chain reaction (using GAPDH as a standard for gene expression), showed an 18-fold increase and was further increased after salt restriction and losartan (all P < .05). Also, adrenal renin activity was raised after nephrectomy and further increased after salt restriction (P < .05) and losartan. Cytochrome P450 aldosterone synthase expression in the adrenal cortex was stimulated by nephrectomy alone and by nephrectomy combined with low salt intake (P < .05), with consequent increases in PA concentrations. In losartan-treated salt-restricted nephrectomized rats, cytochrome P450 aldosterone synthase expression (P < .05 versus nephrectomy alone and nephrectomy plus salt restriction) and PA concentrations were diminished (P < .05) in spite of the observed increases of adrenal renin expression. The AT2-receptor antagonism did not significantly affect PRA, adrenal renin, and aldosterone biosynthesis and production in either intact or nephrectomized salt-restricted rats. These results demonstrate that the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in vivo. This action is mediated primarily via the Ang II AT1-subtype receptors.

Opposite feedback control of renin and aldosterone biosynthesis in the adrenal cortex by angiotensin II AT1-subtype receptors.

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.

Inhibition of aldosterone production by adrenomedullin, a hypotensive peptide, in the rat.

Recently, we conducted in vitro studies and reported that adrenomedullin, a novel hypotensive peptide, inhibits aldosterone secretion by dispersed rat adrenal zona glomerulosa cells. To assess the physiological role of this inhibitory effect, we investigated the effect of adrenomedullin on aldosterone production in vivo. Male Sprague-Dawley rats were fed a normal sodium diet before the experiments. To begin the experimental procedure, we stimulated aldosterone production with a sodium-deficient diet or bilateral nephrectomy. After 3 days of sodium depletion or immediately after nephrectomy, we injected synthetic human adrenomedullin (2.5 nmol/kg SC) and repeated the injection three times at 6-hour intervals. Two hours after the last injection, the rats were decapitated and adrenal capsular tissue was collected. Adrenomedullin had no effect on plasma and adrenal aldosterone concentrations in the rats fed a normal sodium diet. Rats fed a sodium-deficient diet had significantly increased aldosterone concentrations in both plasma (4770.1 +/- 364.3 pmol/L) and adrenal gland (57.34 +/- 3.27 pmol per adrenal). Subsequently, injection of adrenomedullin significantly inhibited increases in concentrations (plasma, 2648.9 +/- 313.2 pmol/L; adrenal, 44.28 +/- 4.94 pmol per adrenal). In nephrectomized rats, increased aldosterone concentrations in plasma and adrenal gland were also significantly inhibited by adrenomedullin. In the second part of the study, plasma renin concentration, adrenal renin activity, plasma corticosterone concentration, serum potassium concentration, and plasma immunoreactive adrenomedullin concentration were examined for adrenomedullin effects. The first four were unaffected, and the last, plasma immunoreactive adrenomedullin, was elevated 15% to 30%. These in vivo results, together with our in vitro data, suggest that adrenomedullin may indeed play a physiological role in the control of blood pressure and electrolyte balance.

Adrenaline cells of the rat adrenal cortex and medulla contain renin and prorenin

The distribution and content of renin in Sprague-Dawley (SD) and transgenic (mREN-2)27 rats (TG) were compared to further define the cellular basis and function of the adrenal renin-angiotensin system. Antibody binding (to rat and mouse renin protein and prosequence) was visualised in serial paraffin sections using an avidin-biotin peroxidase technique. Chromaffin and adrenaline cells were identified by tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase immunoreactivity, respectively. In SD zona glomerulosa (ZG), renin and its prosequence localised to small steroid cells while in homozygous (receiving lisinopril) and heterozygous (untreated) TG, steroid cells labelled in all cortical zones. In addition, throughout the cortex of each strain, large polyhedral adrenaline chromaffin cells occurring singly or in small groups and occasionally in rays labelled for renin and prosequence. Similar large adrenaline cells immunolabelled for all antisera in medulla while other cells were only TH-positive. Total adrenal renin content was 53 times higher in heterozygous transgenics than SD rats and was mainly (74%) prorenin. In SD, 37% of cortical renin was prorenin but in adrenal medulla only active renin was detected. Thus, from present and previous work both renin and prorenin occur not only in mitochondrial dense bodies of the ZG, but also in secretory granules of adrenaline chromaffin cells in both cortex and medulla implying in situ synthesis and paracrine functions.

Developmental studies demonstrate age-dependent elevation of renin activity in TGR(mRen2)27 rats

The objective of the present study was to determine the relationship between plasma renin levels, and the development of hypertension and cardiac hypertrophy in TGR (mREN2)27 hypertensive rats. Systolic blood pressure and left ventricular mass index (LVMI) were measured in transgenic heterozygote and normotensive Sprague Dawley control rats at 25, 35, 45, 55, 65, and 75 days of age together with determinations of plasma active renin and prorenin, and renal and adrenal tissue renin, which were assayed at pH 6.5, 7.4, and 8.5. The systolic blood pressure and the LVMI of the transgenic rats were significantly increased compared to control rats by 55 and 65 days of age, respectively. Plasma active renin of the transgenic rats, measured at physiological pH, was significantly higher from 55 days of age, increasing in parallel with blood pressure and remaining significantly higher than controls at all age groups tested. Assays of both plasma and adrenal renin at various pHs showed a profile of angiotensin I generation that matched mouse renin more closely than that of rat renin. The ratio of angiotensin I (Ang I) generation at pH 8.5 and pH 6.5 was 0.5 for normal rat plasma but was between 3 and 5 for mouse plasma. Plasma prorenin and adrenal tissue renin from transgenic rats exhibited a pH profile consistent with the major portion being mouse renin. However, the low level of kidney renin observed in the transgenic rats exhibited a pH ratio (8.5/6.5) identical to that of normal rat renin (0.5), suggesting that residual renin within the kidney was predominantly of rat origin. These data indicate that plasma renin levels closely parallel the development of high blood pressure and LVMI and show that interpretation of the renin status of this strain is critically dependent on the assay conditions used. Under the conditions used in this study it was found that the TGR(mRen2)27 rat is a high mouse plasma renin model of hypertension.

Reversal of the suppressed kidney renin level in the hypertensive transgenic rat tgr(mRen-2)27 by angiotensin converting enzyme inhibition

The transgenic rat TGR(mRen-2)27 develops severe hypertension with high adrenal renin and low kidney renin. The mechanism of suppressed kidney renin in these animals is still unclear. We investigated the effect of the angiotensin converting enzyme (ACE) inhibitor, perindopril on the renin-angiotensin system in plasma and tissues (adrenal gland and kidney), and the effect of mouse renin antibody on plasma and tissue renin activity before and after perindopril administration. Perindopril lowered blood pressure in the TGR(mRen-2)27 rats from 254.5 +/- 7.4 mm Hg to 154 +/- 7.8 mm hg (n = 8, P < .0001), while blood pressure in the untreated TGR (mRen-2)27 rats increased from 253.7 +/- 8.1 to 276.1 +/- 14.3 mm Hg during the study period. Perindopril significantly suppressed plasma angiotensin II (Ang II) from 19.4 +/- 2.5 pg/mL to 2.6 +/- 0.4 pg/mL, P < .0001, while markedly increasing plasma renin concentration (PRC) from 15.5 +/- 1.8 ng AngI/mL/h to 148.2 +/- 35.5 ng AngI/mL/h, P < .005 and kidney renin from 56.7 +/- 18.1 micrograms AngI/g/h to 827.4 +/- 79.1 micrograms AngI/g/h, P < .0001. However, adrenal renin was not increased. A mouse Ren-2 renin antibody at a 1:1000 dilution that suppresses purified mouse Ren-2 renin activity by 62.6 +/- 3.6% (n = 3, P < .0001) and does not suppress renin activity in plasma and kidney of the Sprague-Dawley rats, suppressed PRC in the untreated TGR(mRen-2)27 rats by 52.3 +/- 3.5% (n = 6, P < .0001). However, it only suppressed PRC in the perindopril treated TGR(mRen-2)27 rats by 7.0 +/- 2.4% (n = 6, P < .05). The antibody suppressed adrenal renin in both untreated and perindopril treated TGR(mREN-2)27 rats by 57.3 +/- 5.4% (n = 5, P < .0001) and 49.7 +/- 2.2% (n = 6, P < .0001), respectively. On the other hand, the mouse antibody suppressed kidney renin in the untreated TGR(mRen-2)27 rats by only 11.0 +/- 3.3% (n = 6, P < .05), and did not suppress kidney renin in the perindopril treated TGR(mRen-2)27 rats (n = 6, P < .0001), respectively. On the other hand, the mouse antibody suppressed kidney renin in the untreated TGR(mRen-2)27 rats by only 11.0 +/- 3.3% (n = 6, P < .05), and did not suppress kidney renin in the perindopril treated TGR(mRen-2)27 rats (n = 6, P < NS). The pH profile of renin activity in plasma confirmed the results of the antibody study. We conclude that in the TGR(mRen-2)27 rats adrenal renin is mainly mouse renin and kidney renin is mainly rat renin. The main sources of circulating renin in the TGR(mRen-2)27 rats are extra-renal tissues, including the adrenal glands, where mouse Ren-2 renin transcripts are highly expressed. The increased circulating renin in perindopril treated TGR(mRen-2)27 rats is rat renin derived from the kidney. The failure of adrenal renin to increase with perindopril suggests that at least in the basal state there is no feedback inhibition as there is in the kidney. The low kidney renin appears to be due to physiological rather than genetic factors.

Morphology and function of the adrenal zona glomerulosa of transgenic rats TGR [mREN2] 27: effects of prolonged sodium restriction.

Heterozygous female transgenic rats for the murine Ren-2 gene (TGR) display a high blood pressure, together with a low kidney and high adrenal renin content. The effects of prolonged sodium restriction on the morphology and secretory activity of adrenal zona glomerulosa (ZG) of TGR and their age- and sex-matched Sprague-Dawley control rats (SDR) were investigated. Under basal conditions, TGR had a moderately hypertrophic ZG, that showed a significantly higher secretion of 18-hydroxylated (18OH) steroids: 18-hydroxy-11-deoxycorticosterone (18OH-DOC), 18-hydroxycorticosterone (18OH-B) and aldosterone (ALDO); ZG cells of TGR showed angiotensin II (AII)-binding site concentrations and ALDO secretory responses to AII similar to those of SDR ZG cells. Prolonged sodium restriction increased plasma ALDO level in both SDR and TGR, and significantly raised the volume of ZG. ZG hypertrophy was due to the increase in both the number and average volume of its parenchymal cells. The secretion of 18OH-steroids was markedly enhanced in both groups of rats; however, in TGR this rise was exclusively due to increases of 18OH-DOC and 18OH-B, while in SDR also ALDO production was enhanced. The yield of non-18OH-steroids was not affected. 11-Dehydrocorticosterone production was not changed in SDR, but doubled in TGR. ZG cells of sodium-restricted SDR and TGR displayed similar increases in their AII-binding site concentration and ALDO secretory response to AII. In conclusion, our present findings confirm that TGR possess a hypertrophic ZG and an elevated secretory capacity o 18OH-steroids, but show only slight differences in ZG and ZG-cell responses to prolonged sodium deprivation.

Regulation of Aldosterone Biosynthesis by Adrenal Renin Is Mediated Through AT 1 Receptors in Renin Transgenic Rats

The transgenic (TG) rat (mREN2)27 is characterized by overexpression of the additional mouse Ren-2d gene in the adrenal cortex with marked suppression of renal renin. We have previously shown that in salt-depleted TG rats enhanced activation of mineralocorticoid biosynthesis is associated with selective stimulation of adrenal renin. To investigate whether the local renin-angiotensin system regulates aldosterone biosynthesis in the adrenal cortex of TG rats, we studied the effects of the AT1-angiotensin subtype receptor antagonist DuP 753 on aldosterone production in 5-week-old TG rats during salt restriction. All the rats (n = 56) were shifted from regular chow to a diet containing only 0.04% NaCl for 1 week. The AT1-receptor antagonist DuP 753 (10 mg/kg per day in drinking water) was administered to 27 of these rats during low-salt diet. Subgroups of rats were killed at 0,4, and 7 days. Low-salt diet increased both adrenal renin activity (from 31 +/- 3 to 77 +/- 4 and 85 +/- 2 ng angiotensin I.h-1.mg protein-1 at 4 and 7 days, respectively; P < .001) and mRNA (by 68.4 +/- 10% and 80 +/- 17% from baseline, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic dexamethasone treatment suppresses hypertension development in the transgenic rat TGR(mREN2)27.

The transgenic rat TGR(mREN2)27 is a monogenetic rat model in hypertension research. Integration of mouse Ren-2 gene into the rat genome led to fulminant hypertension despite suppressed plasma and kidney renin concentrations. Renin is highly expressed in extrarenal tissues, especially throughout the adrenal cortex. Because plasma and urinary corticosteroid concentrations are elevated during the development of hypertension in these rats, we investigated the effect of dexamethasone on blood pressure, adrenal renin and steroid metabolism. A daily injection of 100 micrograms/kg dexamethasone for 8 weeks was capable of suppressing the development of hypertension in the transgenic rats. The same regimen did not alter blood pressure in Sprague-Dawley control rats. Plasma concentrations of adrenocorticotrophic hormone (ACTH)-dependent steroids (corticosterone and 18-hydroxydeoxycorticosterone) decreased markedly in both strains treated with dexamethasone, but more pronouncedly in transgenic rats. Surprisingly, plasma aldosterone concentrations increased exclusively in the transgenic rats, and not in control rats, treated with dexamethasone. The decrease in corticosterone and 18-hydroxydeoxycorticosterone production was accompanied by a decrease in the abundance of the messenger RNA (mRNA) encoding the rate-limiting enzyme in steroidogenesis (P450scc cholesterol side-chain cleavage) and a decrease in the mRNA encoding P450c11 beta (11 beta-hydroxylase). The increase in aldosterone was accompanied by a massive increase in the abundance of the mRNA encoding zona glomerulosa-specific P450c11AS (aldosterone synthase), which was not increased in control rats. We conclude that ACTH-dependent steroids other than the mineralocorticoid aldosterone are responsible for the development of hypertension in the transgenic rat.