(Hypertension. 1995;25:581-586.)
© 1995 American Heart Association, Inc.
Articles |
Renal Nerves, Renin, and Angiotensinogen Gene Expression in Spontaneously Hypertensive Rats
From the Department of Physiology, The Medical School, Birmingham, UK.
Correspondence to Dr E.J. Johns, Department of Physiology, The Medical School, Birmingham B15 2TT, UK.
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Abstract We compared the effect of the renal nerves on renal function, plasma renin activity, and renal renin and angiotensinogen mRNA contents in Wistar rats and spontaneously hypertensive rats (SHR). Rats were anesthetized with sodium pentobarbital, the left kidney was exposed, its nerves were sectioned, the ureter was cannulated, and a flow probe was placed on the renal artery. The renal nerves were stimulated for 1 hour to reduce renal blood flow by 15% and 30%, after which blood was removed for measurement of plasma renin activity, and kidneys were analyzed for renal renin and angiotensinogen mRNA. Frequency-related reductions in filtration rate were similar, from 15% to 50%, as was sodium excretion, from 30% to 70%, in both SHR and Wistar rats. Basal plasma renin activity and responses to nerve stimulation in SHR were approximately half those of Wistar rats (all P<.001). SHR renal renin mRNA concentrations were approximately three quarters those of Wistar rats and were unchanged by either low- or high-level renal nerve stimulation, whereas the higher rate increased renin mRNA approximately threefold (P<.05) in the Wistar rats. SHR renal angiotensinogen mRNA was one quarter that of the Wistar rats and was unaffected by nerve stimulation, whereas in the Wistar rats it was increased threefold (P<.05) by the low but not high level of nerve stimulation. These findings show that whereas the renal nerves are able to modulate hemodynamic and tubular functions relatively normally in SHR, their ability to increase renin release, renal renin, and angiotensinogen mRNA levels is depressed.
Key Words: sympathetic nervous system • gene expression • angiotensinogen • renin • kidney function • RNA, messenger
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Introduction |
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The intrarenal renin-angiotensin system plays an important role in the regulation of both hemodynamic and tubular functions of the kidney,1 and it is now recognized that renin, angiotensinogen, and converting enzyme are all present within renal interstitial fluid and have the potential of generating angiotensin II (Ang II) locally. Renin release from the granular cells of the juxtaglomerular apparatus is regulated by three major mechanisms: the renal sympathetic nerves, mediated by ß1-adrenoceptors; the pressure-sensitive renal baroreceptor; and the macula densa, which is responsive to tubular fluid composition.2 Renin production occurs by a series of intracellular processes whereby expression of the renin gene gives rise to a specific mRNA for preprorenin, which leads to the generation of prorenin, part of which is released directly from the cell via a constitutive pathway, while the major component is incorporated into granules within which mature renin is generated and released via a regulatory pathway.3 Under normal conditions, the rate of production approximately matches that of release, although the level can change in response to long-term stimuli, such as dietary sodium intake, dietary protein intake, and administration of converting enzyme inhibitors.4
There has been relatively little study of the relation between the production and release of renin in response to short-term changes in activity within the renal sympathetic nerves that are known to cause a rapid release of renin. El-Dahr and coworkers5 found that in the rat, renal denervation blunted the increase in renal renin mRNA after long-term ureteral obstruction. Similarly, Page et al6 found that 24 hours after birth, renal renin mRNA levels were lower in denervated than innervated kidneys. Both of these studies therefore demonstrated that tonic activity in the renal nerves could elevate renin gene expression. Furthermore, in vitro studies using mouse renal juxtaglomerular cells, reported by Bruna and coworkers,7 found that incubation with isoproterenol for a minimum of 1 hour caused significant increases in both renin secretion and renin mRNA. We examined the issue more directly in our own studies in the rat8 in which the renal nerves were stimulated for 1-hour periods at different intensities. These findings indicated that the renal nerves had to be stimulated at a level that reduced renal blood flow (RBF) by 30% in order to elevate renal renin mRNA, demonstrating that the kidney had to be subjected to a relatively strong adrenergic stimulus. What is not clear at present is whether the adrenergic control of renin release and production is normal or abnormal in the spontaneously hypertensive rat (SHR).
A number of studies have shown that intrarenal expression of the angiotensinogen gene together with constitutive production and release occurs at the level of the proximal tubule.9 It is likely that the intrarenal level of angiotensinogen will have a major influence on the rate at which Ang II will be generated locally. The renal angiotensinogen mRNA concentrations can be influenced by a number of long-term factors, such as dietary sodium manipulation10 or converting enzyme inhibition,11 suggesting that Ang II itself or sodium load at the proximal tubule might have some regulatory role. Evidence from our own work8 shows that low levels of renal sympathetic activity may increase angiotensinogen gene expression, although at high rates of nerve stimulation, angiotensinogen expression was unchanged. As yet, virtually no studies have been undertaken to examine the relations between changes in nerve activity and angiotensinogen gene expression in the SHR.
The SHR is a rat model genetically derived from the Wistar strain in which the renin-angiotensin system in the kidney is normal or depressed.12 13 This view received further support from Samani et al,14 who showed that in the adult SHR renal renin mRNA levels were depressed compared with those in Wistar rats. Also of interest is an early report by Pratt et al,13 who demonstrated that the response of renal renin mRNA to dietary sodium deficiency was blunted in the SHR. In the present study we examined the effectiveness of the renal nerves in modulating the renal renin-angiotensin system by measuring renal mRNA levels of renin and angiotensinogen, which may reflect expression of the respective genes in the SHR. This was done by stimulating the renal nerves for 1-hour periods at rates that caused predetermined reductions in RBF and comparing changes in renal function, plasma renin activity (PRA), and renal renin and angiotensinogen mRNA levels in SHR and normotensive Wistar rats.
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Methods |
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All animal procedures were permitted under the UK Government Home Office Project License No. PPL40/00274 and Personal License No. PIL 40/00371 issued to E.J.J. Animal care and handling conformed with institutional guidelines. Experiments were performed on three groups of six male SHR and three groups of six male Wistar rats (all 10 to 12 weeks old) that were anesthetized with sodium pentobarbital (60 mg/kg IP) and maintained with a continuous infusion of 12.5 mg/kg per hour IV. After tracheostomy, the left carotid artery was cannulated to allow measurement of blood pressure (Statham P23Db pressure transducer, Gould-Statham Instruments Inc, linked to a model 7 polygraph, Grass Instruments) and removal of blood samples. The left jugular vein was cannulated, and a saline infusion (150 mmol/L NaCl) was begun immediately at 3 mL/h (Braun Secura infusion pump, Braun-Melsungen AG) and continued throughout the experiment. The left kidney was exposed via a retroperitoneal incision, its ureter cannulated, and the renal artery cleared to allow fitting of an electromagnetic flow probe (EP 100 series, Carolina Electronics Inc) for direct measurement of RBF (Carolina FM 501 flowmeter linked to the Grass polygraph). Renal nerve fibers going to the left kidney were isolated distal to the celiac ganglion and then cut. When surgery was complete, a primer solution of 2 mL saline containing inulin (15 mg/mL) was administered intravenously and the saline infusion changed to one containing inulin at 15 mg/mL. Two hours were allowed for stabilization before the experiments were begun.
The experimental protocol consisted of two 15-minute clearance periods, which acted to establish baseline values of cardiovascular and renal function, followed by two 30-minute experimental clearance periods, during which the renal nerves were either stimulated or remained unstimulated. The mean values of the two control and two experimental clearance periods were used in all comparisons. The renal nerves were placed on bipolar silver wire electrodes, and square-wave stimuli were delivered at 15 V with a 0.2-millisecond duration (Grass S8 stimulator). SHR and Wistar rats were subjected to the following procedures: sham, in which the nerves of the left kidney were not stimulated and therefore acted as a time control; low-level renal nerve stimulation, in which the left renal nerves were stimulated at rates to achieve a 15% reduction in RBF; and high-level renal nerve stimulation, in which the left renal nerves were stimulated to achieve a 30% reduction in RBF for 1 hour.
Arterial blood samples (0.35 mL) were collected into syringes, which had been cooled with ice for at least 30 minutes, at the beginning and end of each pair of clearance periods and were immediately centrifuged. Plasma was stored (deep frozen), and erythrocytes were resuspended in an equal volume of saline and infused back into the animal within 5 minutes. Inulin in plasma and urine was assayed as previously described,15 and glomerular filtration rate (GFR) was calculated as the clearance of inulin. Plasma and urinary sodium concentrations were measured with a model 410c flame photometer (Ciba-Corning). At the end of the experiment, a 1-mL blood sample was removed and placed in a tube containing EDTA (5 mg/mL) and immediately centrifuged at 4°C. The plasma was removed and deep frozen for later estimation of PRA. Radioimmunoassay kits for the measurement of PRA were obtained from CIS, UK Ltd, and used as previously described15 ; the results are expressed as nanograms Ang I generated per milliliter of plasma per hour. After the large blood sample was taken, the kidneys were removed within 30 seconds and cut into small blocks that were frozen in liquid nitrogen within 1 minute. The tissues were stored separately in individual vials at -80°C.
Renin and angiotensinogen mRNA levels were analyzed by Northern blot
hybridization analysis. Total RNA was extracted from the kidneys
according to the method of Chirgwin et al16 ; the average
value of total RNA obtained was 1.8±0.1 mg/g of tissue (mean±SEM,
n=72). Each sample of total RNA was incubated for 1 hour at 50°C in a
solution containing 1 mol/L glyoxal and 50% dimethyl sulfoxide at pH
7.0. Samples of glyoxalated total RNA from each kidney, 7.5, 15, and 30
µg, were electrophoresed on 1.5% agarose gels in 10 mmol/L sodium
phosphate (pH 7.0) and transferred to a Biodyne A membrane (Pall
Ultrafine Filtration). The 698-bp Kpn I fragment for rat
renin cDNA17 and the 712-bp BamHI fragment
derived from the rat angiotensinogen cDNA insert of clone pRag
1618 as well as the 420-bp HinfI fragment for
human ß-actin cDNA (National Children's Research Centre, Tokyo,
Japan) were labeled by the oligolabeling method19 in the
presence of [
-32P]dCTP to a specific activity of
1x108 to 7x108 cpm/µg of DNA and used as a
hybridization probe. After prehybridization at 42°C for 12 hours with
hybridization buffer (50% formamide, 5x SSC, 0.1% sodium dodecyl
sulfate, 1% Denhardt's solution, 0.2 mg/mL salmon sperm DNA), the
membranes were transferred into the hybridization buffer containing the
32P-labeled probe. Autoradiograms were prepared with the
use of an intensifying screen at -80°C and were scanned with a
densitometer (LKB Ultroscan XL) for determination of individual band
densities. The absorbances of the hybrid images were plotted against
various amounts of total RNA applied to the membrane, a regression line
was drawn, its slope was calculated, and a correlation coefficient of
more than .9 indicated linearity in the plot that could then be
accepted as a valid measurement. This slope showed the relative level
of specific mRNA and was expressed in arbitrary densitometric units.
After the initial hybridization, the membranes were stripped and
reprobed with ß-actin cDNA, after which each slope of renin or
angiotensinogen in individual rats was normalized against that of
ß-actin from the same kidney sample. Comparisons between groups were
made against the sham group. To undertake comparisons between Wistar
and SHR basal levels, we blotted onto the same membrane pooled total
mRNA samples from the left and right kidneys of each group. After
hybridization with renin cDNA, the membranes were reprobed with
angiotensinogen cDNA and then ß-actin cDNA.
Statistical Analysis
The absolute and percent changes in the text and figures
represent means of changes recorded in individual animals.
Comparisons of the mRNA levels between left and right kidneys and
between groups were made with Student's t test. ANOVA
followed by Dunnett's test was used for multiple comparisons of renal
function, and paired Student's t test was used to test
differences within groups. Values of P<.05 were accepted as
statistically significant; the results are expressed as mean±SEM.
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Results |
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The Table gives the mean baseline values of blood pressure and renal functional variables for all groups of SHR and Wistar rats obtained during the two control clearance periods. Blood pressure and GFR were significantly (P<.001 and P<.05, respectively) higher in SHR compared with Wistar rats, although RBF values were similar in both strains. However, both absolute and fractional sodium excretions were significantly (P<.01) lower in the SHR compared with the Wistar rats.
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The effects of sham, low, and high levels of renal nerve stimulation in both SHR and Wistar rats are shown in Fig 1. It can be seen that in the sham stimulation Wistar rat group, there were minor, insignificant rises in both renal hemodynamic and excretory functions over the course of the experiment. However, during renal nerve stimulation in the Wistar rats, there were significant (P<.05 and P<.001) frequency-related decreases in RBF, GFR, and absolute and fractional sodium excretions. A similar pattern of renal responses was observed in SHR (Fig 1); that is, there was a gradual increase in both renal hemodynamic and excretory variables in the sham group, which did not reach statistical significance, and significant frequency-dependent decreases in RBF, GFR, and sodium excretions in the stimulation groups (Fig 1). The magnitudes of these responses in RBF, GFR, and sodium excretions were similar in both the SHR and Wistar rats whether considered in percent or absolute terms.
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Fig 2 shows that stimulation of the renal nerves in Wistar rats led to 7- and 14-fold increases in PRA levels at the low (P<.001) and high (P<.001) rates of nerve stimulation, respectively. In the sham group of SHR, PRA, at 5.2±1.2 ng/mL per hour, was approximately half that of the corresponding Wistar group (P<.05) and was increased by fourfold and sevenfold by the low (P<.001) and high (P<.001) rates of renal nerve stimulation, respectively. At each rate of renal nerve stimulation, the magnitude of the PRA responses was significantly (both P<.001) smaller in the SHR than in the Wistar rats.
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Fig 3 compares the renal renin and angiotensinogen mRNA content taken from a pooled sample of all kidneys from each of the sham groups. It can be seen that in the SHR, renal renin mRNA concentration was approximately three quarters that of the Wistar rats, and the renal angiotensinogen mRNA value was only approximately one quarter that observed in the Wistar rats. Fig 4 presents the normalized values of renal renin mRNA in response to renal nerve stimulation. It can be seen that activation of the renal nerves at both low and high rates had no effect on renal renin mRNA levels in the SHR (Fig 4), but in the Wistar rats, although the lower rates of renal nerve stimulation had no effect, at the higher rate, renal renin mRNA level was increased significantly (P<.05) by approximately threefold (Fig 4); thus, the response in the SHR was attenuated. The normalized values of renal angiotensinogen mRNA levels are given in Fig 5 and show that in the Wistar rats, although levels were increased significantly (P<.05) when the renal nerves were stimulated at the low rate, they were unchanged at the higher stimulation rate. In the SHR, neither rate of renal nerve stimulation changed the renal content of angiotensinogen mRNA (Fig 5). Fig 6 shows original autoradiograms of the Northern blots for renin, angiotensinogen, and ß-actin from the pooled samples of each group and for the left (denervated) and right (innervated) kidneys of the sham group.
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Discussion |
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The SHR is an experimental animal model of hypertension that shares some features of human essential hypertension and is characterized by the facts that PRA is in the low to normal range12 13 and renal renin content is depressed. Furthermore, it has been shown that the activity within the sympathetic nervous system is elevated in these rats.20 Thus, it is evident that the renin-containing cells of the afferent arteriole are subjected to a number of conflicting signals that determine renin release. One major factor would be the raised blood pressure, which would tend to suppress renin secretion via the renal baroreceptor mechanism. Conversely, the raised renal nerve activity would be causing a stimulation of renin release by a direct action on the granular cells. Furthermore, the renal nerves will act directly on the tubular epithelial cells to increase sodium reabsorption,1 and the decreased filtration rate would decrease the sodium load presented to the macula densa, thereby elevating renin secretion.2 Besides these main mechanisms, it may be possible that in the SHR the ß-adrenoceptors at the renin-containing cells could be downregulated as a consequence of the chronically elevated sympathetic drive. Because of this complex situation, we made an attempt in the present study to determine the effectiveness of the renal sympathetic nerves in causing renin release and whether this resulted in a stimulation of renin mRNA. At the same time, we examined the ability of the renal nerves to modulate angiotensinogen mRNA levels in the kidney.
The blood pressures of the different experimental groups were comparable to those reported previously for this experimental preparation,21 which were higher than those observed in normotensive Wistar rats.8 21 It was apparent that the levels of renal hemodynamics and sodium excretion were comparable to those we and others have observed21 22 in the SHR using similar experimental protocols. An interesting observation was that the rate of sodium excretion, in both absolute and fractional terms, was much lower in SHR than Wistar rats even though the kidneys were operating at a higher pressure, suggesting that the kidneys of these hypertensive rats were in a state of active sodium retention. Stimulation of the renal nerves in the Wistar rats caused a frequency-related reduction in RBF that was associated with somewhat smaller falls in GFR and larger decreases in both absolute and fractional sodium excretions. Essentially similar patterns and magnitudes of renal hemodynamic and tubular responses to nerve stimulation were observed in the SHR. Thus, in terms of kidney function, the renal nerves had a similar effect in both Wistar rats and SHR.
The sham stimulation SHR group had PRA levels that were approximately half those of normotensive Wistar rats; this has been observed previously by others12 13 and would suggest that the basal secretion of renin in the SHR was suppressed, possibly as a result of the elevated systemic and renal perfusion pressures in these hypertensive animals. Stimulation of the renal nerves to reduce RBF by 15% and 30% led to frequency-related increases of PRA in both the SHR and Wistar rats. This renin release could be either caused by a direct action of the renal nerves on the renin-containing cells or a result of the reduction in RBF, or a combination of these factors. It is likely that the main mechanism responsible for the increase in PRA was a direct action of the renal nerves, as in earlier reports it was shown that in the presence of a ß-adrenoceptor antagonist, renal nerve stimulation causing a large23 or modest8 24 reduction in RBF markedly attenuated the increase in PRA. Indeed, in our previous study using Wistar rats subjected to the same experimental procedures,8 we observed that atenolol prevented renin release and activation of renal renin mRNA production during similar levels of renal nerve stimulation. This view is supported by Fray et al,25 who have argued that an increase in renal resistance, as occurs during elevation of renal perfusion pressure or during activation of the renal nerves, decreases the renal baroreceptor–mediated release of renin. More interestingly, the magnitudes of the increase in PRA, fourfold and sevenfold in the SHR, were approximately half those observed in Wistar rats during renal nerve stimulation decreasing RBF to the same extent. The reason for this difference is unclear, but it may be that because of the higher pressure in the SHR, the increased renal perfusion pressure and consequent elevation of renal vascular resistance would act to depress the mechanisms mediating renin release and possibly make the renin-containing cells relatively less sensitive to the neural input to these cells.
A number of long-term (eg, dietary salt depletion) and moderate-term (eg, 4 to 8 hours of angiotensin-converting enzyme inhibitor administration) stimuli are known to elevate both renin release and renal renin mRNA levels.26 In the current study, a much shorter term stimulus was used, a period of 1 hour, and neurally mediated reductions in RBF of 30% for 1 hour led to a threefold to fourfold elevation in renal renin mRNA in the Wistar rats. By contrast, in the SHR even though the same degree of neurally induced reductions in RBF, of 15% and 30%, were used, renal renin mRNA was not changed at either level. It is interesting to speculate why this was so. One possibility may be that because, as reflected by the PRA, relatively less renin was released in the SHR compared with the Wistar rats for the same level of renal nerve stimulation in terms of function, the signals initiating raised expression of the renin gene were not activated to the same extent in the SHR. It may be that a higher rate of renal nerve stimulation is required to elevate PRA levels comparable to those obtained in the Wistar rats before a change in renal renin mRNA levels can be detected. This could lead to the suggestion that some other mechanism attenuated the response in renin gene expression in the SHR. Indeed, Samani and coworkers14 have indicated that renin gene expression is abnormal in many tissues of the SHR, including the kidney. A final consideration is that the chronically elevated renal sympathetic drive in the SHR could have resulted in a downregulation of the ß-adrenoceptors.
The other component of an intrarenal renin-angiotensin system is angiotensinogen, which is necessary for the generation of Ang II locally. It was interesting that in the Wistar rats the renal expression of angiotensinogen gene was elevated at low levels of renal nerve activity although at the higher rate of renal nerve activation the expression of this gene was unchanged compared with the unstimulated kidney. The pattern was markedly different in the SHR, insofar as renal angiotensinogen mRNA levels did not differ in any of the rat groups studied. Again, the reasons for this are unclear. Previous studies26 have shown that hepatic angiotensinogen mRNA levels depend on Ang II, for example, are raised by Ang II infusions and depressed by converting enzyme inhibition. The situation in the kidney is less clear, although Pratt and coworkers13 have shown renal angiotensinogen mRNA to be elevated by dietary sodium depletion in the Wistar rat but not the SHR. The possibility arises that in the SHR the responsiveness of the angiotensinogen gene to physiological stimuli may be depressed.
In this study we set out to describe the effects of activation of the renal nerves for 1 hour on renal function, PRA, and renal renin and angiotensinogen gene expression in the SHR compared with the Wistar rat. The results showed that stimulation of the renal nerves caused approximate frequency-related reductions in RBF, GFR, and sodium output, the magnitudes of which were the same in both SHR and Wistar rats. An important finding was that under these conditions, the rise of PRA in the SHR was only half that obtained in the Wistar rats. Furthermore, in the Wistar rats the expression of the renin gene was elevated approximately threefold at the higher rate of renal nerve stimulation, whereas it remained unchanged in the SHR at both the high and low rates. Although the renal angiotensinogen mRNA levels in the Wistar rats were elevated at the low but not high rates of renal nerve stimulation, in the SHR the level of renal angiotensinogen gene expression remained unaltered. The findings demonstrate that in the SHR the neural influences on the expression of the renin and angiotensinogen genes are depressed. This may be indicative of abnormalities within the cell determining expression of these genes, or alternatively, the renin-releasing cells are subjected to conflicting signals, that is, raised renal sympathetic nerve activity and raised perfusion pressure, which together determine the overall response of the cells.
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Acknowledgments |
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Akio Nakamura was a recipient of a British Heart Foundation Overseas Research Fellowship. This study was supported in part by a grant from Pfizer (Kent, UK). We thank Dr Hirwaki Ohkubo for the gift of the pRag 16 for rat angiotensinogen cDNA and Dr Akiyoshi Fukamizu for the Kpn I fragment for rat renin cDNA.
Received August 15, 1994; first decision September 14, 1994; accepted November 28, 1994.
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