Effects of growth hormone on renal renin gene expression in normal rats and rats with myocardial infarction

Martin C. Kammerl, Daniela Grimm, Caroline Nabel, Frank Schweda, Matthias Bach, Sabine Fredersdorf, Harald Piehler, Stephan R. Holmer, Günter A. J. Riegger, Eckhard P. Kromer and Bernhard K. Krämer

Klinik und Poliklinik für Innere Medizin II, University of Regensburg, Regensburg, Germany



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Published data regarding effects of growth hormone (GH) on the renin system are controversial. The aim of this study therefore was to evaluate the effects of GH on the renin system in normal rats and rats with myocardial infarction (MI).

Methods. Normal rats received 2, 5, or 10 IU GH/kg/day or vehicle subcutaneously for 4 weeks. Furthermore rats with MI were randomized to receive 2 IU GH/kg/day or vehicle for 4 weeks. Subdivision into MI groups (mild, moderate, and large) was by histological determination of infarct size. Renal renin gene expression was assessed by RNAase protection assay and plasma renin activity by radioimmunoassay. In addition, isolated mouse juxtaglomerular cells were exposed to GH for 20 h, and renin secretion rates were assessed.

Results. GH treatment in normal rats for 4 weeks increased body weight, and kidney weight to body weight ratio, but did not affect renin secretion and renal renin gene expression. In rats with large MI, renal renin gene expression increased about fourfold, but was unchanged in rats with small and moderate MI as compared to normal rats. In rats with MI, body weight decreased and this decrease was partially reversed by GH treatment. GH treatment did not change renal renin gene expression, and renin secretion in rats with MI. Renin secretion of isolated juxtaglomerular cells was unaffected by GH.

Conclusions. Our study demonstrates that GH treatment has no significant effect on renin secretion and on renal renin gene expression in normal rats and in rats with stimulated renin system due to MI in vivo. In isolated juxtaglomerular cells in vitro, renin secretion was also unaffected by GH.

Keywords: blood pressure; experimental myocardial infarction; growth hormone; plasma renin activity; renal renin expression; renin regulation



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Growth hormone (GH) treatment is well established for adult patients with GH deficiency, and children with chronic renal failure, where it increases the velocity of growth [1]. In addition, increasing numbers of normal short-stature children are receiving GH treatment [2]. Furthermore, in patients with impaired left ventricular function, treatment with GH is evaluated in clinical trials [3]. During GH treatment, water and sodium retention has been reported [4,5]. This is in accordance with a decreased plasma and extracellular volume in GH-deficient adults, where extracellular volume normalized or clinical signs of sodium retention became evident, and plasma renin activity increased with GH treatment [6]. In another study with GH- deficient adults, plasma renin activity and blood pressure was unchanged after 1 week and 6 months of GH replacement, whereas total body water and erythrocyte sodium content increased significantly after 6 months [7]. In hypophysectomized rats, the known hypotension has been suggested to be due to an impaired renin secretory response to a reduction of renal perfusion pressure [8]. This defect could be reversed by a single injection of GH. Sodium retention with GH treatment has repeatedly been suggested to be due to an activation of the renin–angiotensin system in healthy and GH-deficient adults, and short normal children [5,6]. Furthermore, in a study involving healthy adult males, blockade of the renin–angiotensin system using captopril and spironolactone both prevented sodium and fluid retention [9]. However, the role of a GH-activated renin–angiotensin system has been controversial, with no change of plasma renin activity but an altered glucocorticoid sensitivity in a study in GH-deficient adults [10]. In rats receiving long-term GH treatment, no changes in renal electrolyte clearances and of plasma renin activity during the first 4 days of treatment were observed [11]. In children with short stature after 3, 6, 9, and 12 months or 1 week and 4 months of GH treatment, plasma renin activity and aldosterone were unchanged without any evidence of sodium retention in one study or only a slight and transient increase in the other study [12,13]. Unexpectedly, Folkow et al. [14] demonstrated in hypophysectomized rats even an increase in plasma renin activity, although the response to renal artery clipping was impaired. GH administration for 14 days in healthy adult men resulted in an increase in extracellular volume but no change of plasma angiotensin or aldosterone concentrations [15]. In patients with acromegaly, plasma renin activity at baseline was normal, but the increase of plasma renin activity with stimulatory manoeuvres was impaired [16]. The distribution of low-renin hypertension in patients with acromegaly was not different to the general hypertensive population [17].

In view of these highly discrepant results, the purpose of our investigation was threefold: (i) to examine in normal rats effects of ascending doses of GH during subchronic treatment on renal renin gene expression, and on renin secretion; (ii) to investigate the effects of GH on renal renin gene expression and on renin secretion following experimental MI with an already stimulated renin–angiotensin system, since a further stimulation of renin secretion might be deleterious with pre-existing impaired left ventricular function; and (iii) to study the effects of GH on renin secretion in isolated juxtaglomerular cells in vitro.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Animals
Normotensive, male Wistar rats (body weight (BW) 180–200 g, age 6 weeks) were obtained from Charles River Wiga Inc. (Sulzfeld, Germany). They were maintained on standard rat chow (H1003, Alma KG, Kempten, Germany) with water ad libitum. All animals were individually housed in a 12-h dark/light cycle controlled room. The protocols had been approved by the local standing committee on animal research. The investigation conforms to the Guide for the Care and Use of Laboratory Animals, published by the US National Institute of Health (NIH Publication No. 85–23; revised 1985). The present investigation is part of a study of myocardial effects, cardiomyocyte and extracellular matrix protein remodelling of GH treatment in rats following experimental MI [18].

GH dosing and study protocol
Three different dosages of recombinant human GH were administered: 2, 5 and 10 IU/kg/day (n=15 for each group). Fifteen animals received vehicle. Furthermore, rats with experimental MI were randomized to receive daily subcutaneous injections of vehicle or 2 IU GH/kg/day. GH solutions (1 U=0.4 mg; Serono Pharma GmbH, Munich, Germany) were prepared using a provided vehicle immediately before subcutaneous injections under sterile conditions. After 28 days, the rats were anaesthetized with thiopental sodium (100 mg=kg i.p.) prior to performing echocardiography and haemodynamic measurements. Immediately after the haemodynamic measurements, the animals were sacrificed by decapitation. Blood was collected from the carotid arteries for determination of haematocrit and PRA. Kidneys were removed rapidly, weighed, cut in half, frozen in liquid nitrogen, and stored at -80°C until isolation of total RNA.

Experimental myocardial infarction
Rats were intubated under general anaesthesia (methohexital 80 mg/kg ip) and placed on a respirator. The heart was exposed via a left-sided thoracotomy, and the anterior descending branch of the left coronary artery was ligated between the pulmonary outflow tract and the left atrium as described previously in more detail [18].

Haemodynamic measurements
Central haemodynamic parameters were measured under light anaesthesia via the right carotid artery (aortic pressure, LV pressure) and right jugular vein (right atrial pressure) using a 2-French catheter pressure transducer (Millar Instruments, Houston, TX, USA) as described previously [18].

Infarct size was determined histologically using serial slices of the left ventricle [18].

Tissue preparation
Isolation of RNA.
Total RNA was isolated according to the protocol of Chomczynski and Sacchi [19].

Determination of preprorenin mRNA.
Renin mRNA was determined by RNAase protection assay in rat kidneys using 20 g RNA as described in detail previously [2020,21]. Data are reported as ratio netto c.p.m. renin mRNA/netto c.p.m. actin mRNA.

Determination of actin mRNA.
Actin mRNA was determined by RNAase protection assay as previously described [21].

Biochemical studies
Between four and eleven rats from each group were randomly selected and killed by decapitation. Trunk blood was collected for determination of plasma renin activity. Renin activity was measured by its ability to generate angiotensin I, measured by a commercially available radioimmunoassay (Sorin Biomedica, Düsseldorf, Germany).

Isolation and primary culture of mouse juxtaglomerular cells
Mouse juxtaglomerular cells were isolated as described previously [20]. After 20 h of primary culture the medium was removed, washed once with fresh culture medium, and then culture medium with different concentrations of GH and/or 3 µmol/l forskolin, and/or 100 nmol/l endothelin-1 was added for 20 h. Renin secretion was measured as fractional release of total renin, i.e. renin activity released (into the supernatant)/total renin activity (supernatant+intracellular (released by lysis of cells with Triton X-100)).

Statistical analysis
Comparisons between multiple groups were assessed by ANOVA including a modified least-significant difference (Bonferroni) multiple range test to detect significant differences between two distinct groups, which were further analysed using the Mann–Whitney U test. Results are expressed as mean±SEM. Statistical significance was accepted at P<0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Body weight, kidney weight, and blood pressure
The effects of three dosages of GH were studied in 60 normal rats that received subcutaneous injections of GH (2, 5 or 10 IU/kg/day) or vehicle for 28 days [18]. There were small but significant (P<0.01) increases of body weight in all GH-treated rats: 2 IU/kg/day, 37 g; 5 IU/kg/day, 35 g; 10 IU/kg/day, 30 g in comparison to vehicle-treated rats: 398±3 g. Kidney weight to body weight ratio increased in GH-treated rats (P<0.01 vs vehicle; Table 1Go). However, no dose-response curve could be observed either for GH-induced increases of body weight or for kidney weight to body weight ratio in the dose range of GH studied.


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Table 1. Growth hormone in normal rats: systolic and diastolic blood pressure, kidney weight to body weight ratio, and plasma renin activity

 
One hundred and forty rats with MI were randomized to vehicle or GH treatment [18]. According to the size of MI, rats were divided into three groups: small MI (<20% of LV circumference), n=21 (vehicle) and n=19 (GH); moderate MI (20–40%), n=18 (vehicle) and n=21 (GH); and large MI (40–60%), n=21 (vehicle) and n=20 (GH).

Rats with MI had a significantly lower BW (small MI -38 g, moderate MI -25 g, large MI -63 g) as compared to sham-operated rats (407±5 g), and treatment with GH attenuated these findings (small MI -3 g, moderate MI -16 g, large MI -9g). Relative kidney weight was unaltered: small MI 7.4±0.3, moderate MI 7.7±0.4, large MI 7.3±0.3; small MI+GH 7.3±0.2, moderate MI+GH 7.5±0.2, large MI+GH 6.8±0.3.

Systolic and diastolic blood pressures were not changed by increasing doses of GH in normal rats (Table 1Go). Systolic blood pressure was not affected by MI or GH treatment in comparison to sham-operated rats (137±4 mmHg): small MI+vehicle +8 mmHg, small MI+GH +2 mmHg, moderate MI+vehicle +9 mmHg, moderate MI+GH -2 mmHg, large MI+vehicle -4 mmHg, large MI+GH -2 mmHg.

Renal renin gene expression and plasma renin activity
In normal rats renal renin gene expression was unaffected by 2, 5, or 10 IU/kg/day GH administration (n=7–8 in each treatment group) in comparison to vehicle treated rats (n=7) for four weeks (Figure 1Go). In rats with large MI (n=8) renal renin gene expression increased nearly 4-fold in comparison to sham-operated rats (n=8), whereas renal renin gene expression was unchanged in rats with small (n=6) or moderate MI (n=7) (Figure 2Go). Similarly, in rats with large MI treated with GH (n=8), renal renin gene expression increased nearly threefold in comparison to sham-operated rats (n=8), whereas renal renin gene expression was unchanged in rats with small (n=6) or moderate MI (n=8) (Figure 3Go). PRA in normal rats was not affected by increasing doses of GH (Table 1Go). In small groups of rats with MI, PRA tended to increase in large MI both without GH treatment (small MI (n=4) 4.1±2.0 ng/h/ml; moderate MI (n=3) 3.6±1.3 ng/h/ml; large MI (n=4) 6.7±2.1 ng/h/ml) and with GH treatment (small MI (n=2) 4.5±1.2 ng/h/ml; moderate MI (n=5) 4.2± 0.8 ng/h/ml; large MI (n=4) 11.4±4.8 ng/h/ml) when compared with small or moderate MI.



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Fig. 1. Renal renin gene expression given as c.p.m. renin/c.p.m. actin ratio in normal rats treated with 2, 5, or 10 IU GH/kg/day or vehicle for 28 days.

 


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Fig. 2. Renal renin gene expression in rats with small, moderate or large experimental myocardial infarction or in sham-operated rats with concomitant vehicle administration. #P<0.05 vs sham, +P<0.05 vs small MI, *P<0.05 vs moderate MI.

 


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Fig. 3. Renal renin gene expression in rats with small, moderate or large experimental myocardial infarction or in sham-operated rats with concomitant GH treatment (2 IU/kg/day). #P<0.05 vs sham-operated.

 

Renin secretion in juxtaglomerular cells in vitro
Basal renin secretion, and renin secretion after 20 h of incubation with 3 mol/l forskolin, 3 mol/l forskolin+100 nmol/l endothelin-1, 0.1 IU/l GH, 3 µmol/l forskolin+0.1 IU/l GH, and 3 µmol/l forskolin+0.1 IU/l GH+100 nmol/l endothelin-1 are given in Figure 4Go (mean±SEM of four independent cell preparations, each comprising four culture wells/condition (n=16)). The well-known renin stimulatory effects of forskolin via adenylyl cyclase activation, and inhibitory effects of endothelin-1 on cAMP-stimulated renin secretion are obvious; however, GH administration does not affect renin secretion either at baseline or after stimulation with forskolin or inhibition by endothelin. Furthermore, 0.01 IU/l GH, 1 IU/l GH, and 10 IU/l GH did not affect either basal or forskolin-stimulated renin secretion for isolated juxtaglomerular cells. Thus GH at concentrations of 0.01, 0.1, 1.0, and 10 IU/l does not affect renin secretion from isolated juxtaglomerular cells in vitro.



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Fig. 4. Basal renin secretion rate, and renin secretion rate after 20 h of incubation with 3 µmol/l forskolin, 3 µmol/l forskolin+100 nmol/l endothelin-1, 0.1 IU/l GH, 3 µmol/l forskolin+0.1 IU/l GH, and 3 µmol/l forskolin+0.1 IU/l GH+100 nmol/l endothelin-1 in primary cultures of isolated mouse juxtaglomerular cells. #P<0.05 vs basal renin secretion, +P<0.05 vs renin secretion in GH incubated cells.

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The effects of GH administration on sodium retention and stimulation of the renin–angiotensin system have been extensively studied, yielding highly controversial results [4–17]. Part of this discrepancy might be due to the dose of GH used, the timing of measurements (e.g. during acute vs subchronic vs chronic GH treatment), and the type of measurement (e.g. plasma renin activity vs plasma aldosterone vs plasma angiotensin II vs renin gene expression), the patient (e.g. adult vs children/healthy control vs GH deficient vs acromegaly), or the species (human vs rat) studied [4–17]. Since most of the effects of GH are mediated by IGF-1, the effects of IGF-1 on the renin system are of interest in the context of our study. Jaffa et al. [22] suggested that 2-h infusions of a high dose of IGF-1 increased renal renin gene expression in diabetic rats. In addition, renin secretion from rat renal cortical slices was stimulated by IGF-1 in normal rats, and diabetic rats (only at up to 100-fold higher concentrations than in normal rats) [23]. However, in patients with essential hypertension, high circulating IGF-1 levels have been correlated with low-renin hypertension [24]. Overall, these published data concerning the interaction of IGF-1 and the renin–angiotensin system are as controversial as the data about the interaction of GH with the renin– angiotensin system [4–17].

The present study demonstrates that renin secretion and renal renin gene expression in normal rats and in rats with small, moderate, or large MI is not affected by GH treatment with effective doses for 28 days. GH treatment had significant effects on body weight, kidney weight to body weight ratio, and left ventricular hypertrophy in normal rats, and on body weight, cardiomyocyte hypertrophy, and left ventricular performance in rats with MI, suggesting the use of effective doses of GH [18]. The somewhat smaller increase in renal renin gene expression in rats with MI treated with GH in comparison to vehicle-treated rats with MI may be explained by the beneficial effects of GH on left ventricular function, thereby reducing neurohumoral stimulation [18]. Overall, our data do not suggest that subchronic growth hormone treatment in rats with experimental MI is affecting the renin system. No increase in blood pressure in normal rats, and in rats with MI treated with GH, also argues against a stimulation of the renin system or sodium retention. Furthermore the incubation of isolated juxtaglomerular cells with GH in vitro for 3 and 24 h both in unstimulated and forskolin-stimulated preparations did not affect renin secretion. The concentrations of GH used (0.01–10 IU/l) for these cell culture experiments cover the range of concentrations reached in normal man and during GH substitution [25,26]. The presence of GH receptors on renal juxtaglomerular cells has not been formally demonstrated; however, it appears to be very likely since GH receptors have been shown ubiquitously on vascular smooth-muscle cells [27].

The data of the present study are reassuring with regard to the potential for stimulation of the renin system as a side-effect of GH administration, for example in adult patients with GH deficiency, in children with renal failure, and especially in patients with heart failure treated with GH.

Taken together, we were able to demonstrate that subchronic GH treatment for 4 weeks with effective doses in normal rats and rats with small, moderate, and large MI does not stimulate the renin system in vivo, and that GH also does not affect renin secretion from isolated juxtaglomerular cells in vitro.



   Acknowledgments
 
This study was supported by grants from the Else-Kröner-Fresenius-Stiftung, and from Serono Pharma GmbH, Unterhaching, Germany (Study-no. GF 7198). This study is part of the thesis of MB and HP. The authors thank Prof. Armin Kurtz, Physiologie, University of Regensburg for critical reading of the manuscript and for helpful suggestions.



   Notes
 
Correspondence and offprint requests to: Dr B. K. Krämer, Klinik und Poliklinik für Innere Medizin II, University of Regensburg, D-93042 Regensburg, Germany. Back



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 Subjects and methods
 Results
 Discussion
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Received for publication: 10. 8.99
Revision received 20. 1.00.



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