Antiglucocorticoid RU38486 reduces net protein catabolism in experimental acute renal failure
© Mondry; licensee BioMed Central Ltd. 2005
Received: 23 September 2004
Accepted: 17 February 2005
Published: 17 February 2005
In acute renal failure, a pronounced net protein catabolism occurs that has long been associated with corticoid action. By competitively blocking the glucocorticoid receptor with the potent antiglucocorticoid RU 38486, the present study addressed the question to what extent does corticoid action specific to uremia cause the observed muscle degradation, and does inhibition of glucocorticoid action reduce the protein wasting?
RU 38486 was administered in a dose of 50 mg/kg/24 h for 48 h after operation to fasted bilaterally nephrectomized (BNX) male adult Wistar rats and sham operated (SHAM) controls. Protein turnover was evaluated by high performance liquid chromatography (HPLC) of amino acid efflux in sera from isolated perfused hindquarters of animals treated with RU 38486 versus untreated controls.
Administration of RU 38486 reduces the total amino acid efflux (TAAE) by 18.6% in SHAM and 15.6% in BNX and efflux of the indicator of net protein turnover, phenylalanine (Phe) by 33.3% in SHAM and 13% in BNX animals as compared to the equally operated, but untreated animals. However, the significantly higher protein degradation observed in BNX (0.6 ± 0.2 nmol/min/g muscle) versus SHAM (0.2 ± 0.1 nmol/min/g muscle) rats, as demonstrated by the marker of myofribrillar proteolytic rate, 3-Methylhistidine (3 MH) remains unaffected by administration of RU 38486 (0.5 ± 0.1 v. 0.2 ± 0.1 nmol/min/g muscle in BNX v. SHAM).
RU 38486 does not act on changes of muscular protein turnover specific to uremia but reduces the effect of stress- stimulated elevated corticosterone secretion arising from surgery and fasting. A potentially beneficial effect against stress- induced catabolism in severe illness can be postulated that merits further study.
As part of the complex uremic metabolic syndrome, pronounced disturbances of carbohydrate and lipid metabolism are commonly observed, as are pathologic changes of amino acid and protein turnover . An increased net protein degradation in uremia was seen as early as 1949 by Persike and Addis, and in the same year, Bondy et al.  showed that adrenal hormones are involved therein. These early findings were validated in the late eighties by Schäfer et al. [4, 5] who postulated a leading role for glucocorticoids as cause of the observed changes. Schäfer et. al used the experimental approach of inhibiting activation of the glucocorticoid receptor by enteral application of the potent glucocorticoid antagonist RU 38486 in acutely uremic rats  and found a decrease both in the accumulation of 3-methylhistidine, an amino acid that is produced in actomyosine catabolism and is not further metabolized, and in the activity of myofibrillar protease. However, while an effect of RU38486 on liver gluconeogenesis and urea synthesis in uremia could be demonstrated [7, 8], so far there is no proof of a direct action of RU38486 on muscle metabolism in uremia. To address this problem, the present study made use of the classical experimental design of the isolated perfused hindquarter of the rat , in which roughly 40% of the rat body's total muscle mass can be evaluated under closely defined in vitro conditions.
With this experimental design and by comparing sham-operated and bilaterally nephrectomized animals, the present study looked at the question to what extent does corticoid action specific to uremia cause the observed muscle degradation, and does inhibition of glucocorticoid action reduce the protein wasting?
Animal experimentation was carried out on male Wistar rats, aged 11–15 weeks, weighing 217–225 g, from the animal experimentation facilities of Heinrich Heine University, Düsseldorf. Permission to use animals for experimentation was given by Regierungspräsident Düsseldorf, file nr. 26.4203.1-217/87 according to German federal law. Surgery for nephrectomy, sham nephrectomy and preparation for perfusion was carried out under narcosis with hexobarbital (EVIPAN- Na: 15–20 mg/ 100 g BW).
Bilateral nephrectomy was performed using a dorsal access, ligation of renal vessel string, and excision of the kidney, leaving the adrenal glands in place. Sham operated animals underwent the same manipulations except for the ligation and excision. After surgery, animals were fasted for 48 h until perfusion. Nephrectomized animals had access to drinking water on the day of surgery for 8 hours, then were deprived of liquid to avoid lung edema. Sham animals had free access to drinking water throughout.
Animals were randomly assigned to one of four groups: bilaterally nephrectomized (BNX) and sham operated (SHAM) treated with RU38486 and untreated BNX and SHAM animals. For treatment, RU38486 was dissolved in phenylmethanol, then mixed with sesame oil to form a milky suspension which was injected into subcutaneously into the lateral abdomen in three subdoses within 24 h, adding up to a total dose of 5 mg/100 g/BW.
48 h after initial surgery, animals were narcotized and prepared for perfusion as previously described.
The hindquarter was linked to the recirculation system after full passage of 70 ml of pre- perfusion medium, as shown in illustration 1. The pre- perfusion medium was discarded and not used for the recirculation experiment.
The perfusion was carried out with a half- synthetic medium on the basis of Krebs- Ringer- bicarbonate buffer (KRB), pH 7.38 . Oxygen carriers were calf erythrocytes prepared from fresh calf blood sampled two days before experimentation and maintained with 300 mg/l Ampicillin and 220 ml/l citric acid/ glucose stabilizer. Bovine albumine maintained the physiologically correct oncotic pressure. 10-6 mmol/l phentolamine were added to avoid vessel contractions.
During perfusion, the arterial pH and perfusate oxygenation were monitored using a pH- meter and a total oxygen content analyzer (LEX- O2- CON, Lexington Instr., Mass., USA). At the beginning and end of perfusion, plasma samples were frozen for amino acid analysis. Amino acid analysis by HPLC was carried out using 25 μl of deproteinized perfusate sample, mixed with o-phthaldialdehyde (OPA)/3-mercaptopropionic acid to form OPA- adducts that were separated on a reversed phase column and measured by fluometry. Quantification was done by comparison with a standard amino acid mix including 3-methylhistidine. Of the 20 proteinogenic amino acids, cysteine, proline, and asparic acid were not included in HPLC analysis.
Statistical analysis was done using the "Student" t- test for ungrouped, non- paired data with f = n1 + n2-2 and a significance level of p < 0.05.
Loss of body weight (BW)
Body weight (BW) at day of surgical intervention (OP) and perfusion (EX). Values are gram ± standard deviation. No significant intergroup differences.
BW [g] at OP
BW [g] at EX
Weight loss [g]
SHAM (n = 6)
223.67 ± 8.02
188.17 ± 7.28
35.5 ± 5.3
BNX (n = 6)
217.33 ± 13.81
201.67 ± 11.91
15.7 ± 4.8
SHAM + RU (n = 5)
223.60 ± 9.21
196.00 ± 9.70
27.6 ± 5.9
BNX + RU (n = 5)
225.20 ± 5.36
213.00 ± 7.35
12.2 ± 4.8
Dry weight (DW) in % of total tissue weight and hydration (Hy) at day of perfusion in ml/ g of total tissue weight. Average values ± standard deviation. Intergroup differences with significance levels of: *p < 0,001; #p < 0,05.
SHAM + RU#
BNX + RU#
24.41 ± 1.46
21.07 ± 0.98
24.26 ± 1.14
22.10 ± 1.46
0.761 ± 0.015
0.795 ± 0.010
0.762 ± 0.012
0.784 ± 0.015
Oxygen utilization and development of acidosis
Oxygen utilization in the perfused muscle tissues is roughly the same in all four groups (data not shown) and equal to in vivo data previously reported  from rats after 24 hour fasting. As expected, pH dropped significantly lower during perfusion in the nephrectomized groups (SHAM: 7.378 ± 0.033, BNX 7.321 ± 0.018, p = <0.01; SHAM + RU 7.4 ± 0.031, BNX + RU 7.312 ± 0.013, p < 0.001).
Parameters of amino acid and protein metabolism
Total amino acid efflux (TAAE) and release of 3-methyl histidine (3 MH) in serum from isolated perfused rat hindquarter at 60 min. perfusion. Values given in nmol/min/g muscle + standard-deviation. Intergroup differences with significance of: #p < 0,01; *p < 0,005; ~, $p < 0,001.
SHAM + RU
BNX + RU
65.05 ± 5.88*
71.83 ± 5.02#
52.98 ± 2.96*
60.61 ± 5.62#
0.2 ± 0.09~
0.55 ± 0.15~
0.18 ± 0.06$
0.53 ± 0.07$
Acute renal failure is a catabolic state, and unfortunately the inherent acceleration of protein breakdown cannot be suppressed effectively by provision of exogenous nutritional substrates . The situation is multicausal. Unspecific mechanisms induced by the process of acute disease, underlying illness and associated complications are just one side of the problem. On the other, one observes specific uremic effects, insulin resistance, hormonal derangements, metabolic acidosis, circulating proteases and other inflammatory mediators together with effects induced by the acute loss of renal function and the type and intensity of renal replacement therapy [1, 15–17].
One factor that has for long been associated with the disturbances of protein metabolism is glucocorticoid action. The first observations date back to the nineteen-forties, when Persike and Addis  reported an increased urea- nitrogen production in experimental uremia, and Bondy and coworkers  demonstrated that adrenal hormones were involved in this dysregulation. Half a century later, it is still not fully understood to what extent steroid hormone action is responsible for the catabolic situation observed in renal insufficiency. It has been shown that administration of high doses of glucocorticoids to adrenalectomized rats resulted in decreased protein synthesis, increased protein degradation, and a negative nitrogen balance . In patients with chronic renal failure, a positive correlation between muscle proteolysis and the plasma cortisol level has been observed . The in vivo influence of both glucocorticoids and metabolic acidosis on muscle proteolysis has been elucidated in whole- body leucine turnover studies in adrenalectomized rats . These findings indicate that glucocorticoids play an important role in net protein degradation. Price formulated this so: "glucocorticoids are required but not directly responsible for the acidosis-induced increase in the mRNAs encoding proteins of this degradative pathway".
In order to evaluate the relative importance of glucocorticoid action on protein metabolism in acute renal failure, an experimental setting was chosen that allowed to study glucocorticoid action indirectly by selective blockade of the glucocorticoid receptor with the potent antiglucocorticoid RU38486, a substance that binds to the receptor without activating the further process of transcription . Parenteral administration of a total of 50 mg/kg BW/ d of RU38486 allowed to avoid additional irritation of the animals by a gastric catheter in the postoperative phase. Relevant action of RU38486 has been observed in enteral substitution at a dose of 20 mg/kg BW/d . The degree to which RU 38486 blocks the glucocorticoid receptor depends very much on the mode of application, and the target tissue. While a recent study shows that 80% of glucocorticoid receptors are blocked in rat muscle following oral application of mifepristone of 50 mg/ kg BW, Kim et al. demonstrated effective blocking of glucocorticoid receptors in rat brain following subcutaneous application of 80 mg/ kg over two days. Schaefer et al., on whose experimental set- up the present study was modeled, had reported significant effects of an oral dose of 20 mg/ kg on muscle. In view of this, the choice for the experimental procedure seems justified as the present study uses a substantially higher dose.
The isolated perfusion procedure introduced by Ruderman is well established for the representative study of muscle metabolism. In this setting, the perfused muscle mass is approximately 40% of the total muscle mass. Taking into consideration the different metabolic requirements of the perfused tissues, roughly 90% of oxydative metabolism occurs in the muscle, making this experimental setting truly a skeletal muscle preparation that permits the observation of even very discrete metabolic changes during reperfusion.
In the given experimental setting, it is difficult to account for the in detail contribution of protein degradation, amino acid intermediate metabolism, and protein synthesis. Factors that modify the efflux are transport systems in the cell membrane [26–28], which can be concentration- dependent (system L) or acting against the concentration gradient (system A), and the intermediary metabolism within the muscle cells. Numerous previous assessments of the metabolic situation in the isolated perfused hindlimb demonstrate that these factors are relatively minor contributors, while amino acid efflux is nearly exclusively characterized by the net balance of protein metabolism both in anabolic and catabolic situations[12, 30–34]. It is mostly due to changes in skeletal muscle, with only minor contributions from other tissues in this preparation [35–37].
Amino acid release from the isolated perfused hindlimb. P- values indicate significant differences in the comparison between sham- operated and nephrectomized animals, either without or with RU 38486 treatment. A: p- value for SHAM vs. SHAM + RU; B: p- value for BNX vs. BNX + RU; C: p- value for SHAM vs. BNX; D: p- value for SHAM + RU vs. BNX + RU.
By contrast, in the comparison of the two groups treated with RU38486, the amino acid release remains increased in nephrectomized animals, albeit to a lesser extent, stressing the very point that glucocorticoids are only one of several factors that contribute to the net protein wasting. Chronically uremic rats with increased corticosterone- secretion  showed a less pronounced increase in protein degradation when acidosis was balanced while the defective protein synthesis remained unchanged. In the present experimental setting, acidosis evolving during perfusion was not corrected for. Acidosis and glucocorticoid action are seen as concomitant factors in the activation of the ubiquitin- proteasome pathway of muscle proteolysis , and a pH- responsive element in the promoter region for the ubiquitin- proteasome pathway has been reported . In the situation of uncorrected acidosis, it therefore seems likely RU 38486 may have had an inhibitory effect on the corticoid- induced decrease in protein synthesis without influencing the proteolytogenic effects of other putative agents.
This presumption is supported by the finding that RU 38486 had no effect on the efflux of 3-methylhistidin. While this result is in contrast to Schäfer et al. [6, 8], Lowell et al. found no reduction of the efflux of 3-methylhistidin after adrenalectomy in the perfused hindquarter of fasted animals , and in rats with chronic uremia, RU38486- resistant protein catabolism with unchanged release of 3-methylhistidin has been demonstrated in vivo by Teschner . As responsiveness of protein synthesis and degradation to amino acid availability seem to be regulated differentially  and activation of glucocorticoid- mediated proteolysis occurs only at relatively elevated hormone levels  compared to the inhibition of protein synthesis , it seems possible to speculate that RU38486 may have a more pronounced effect on net protein catabolism at substantially higher doses.
The presented data fail to show that RU38486 inhibits glucocorticoid action in the specific uremic setting while it clearly reduces the elevated net protein catabolism compared to non- operated animals. This suggests that glucocorticoid mediated protein wasting in acute uremia is rather a by- product of the overall stress, in the present experimental setting caused by surgery and fasting, than due to an independent action specific to uremia.
While this finding abolishes hopes to counteract muscle wasting in uremia by administration of an anticorticoid drug and indirectly rather stresses the well described clinical importance of a balanced acid- base status, it may open speculation about the usefulness of RU486 in post- traumatic states and severe illness.
Both sham- operated and nephrectomized animals show an increase in net protein catabolism. RU38486 clearly reduces the net protein wasting in both groups, but the increase in net protein catabolism observed over sham- operated animals remains unchanged in nephrectomized rats. The effect of antiglucocorticoid RU38486 may be attributed to an inhibition of fasting and operative stress- induced cortisol action which, even when within the physiological range, promotes increased protein turnover , and to a protective effect against the inhibition of protein synthesis. While RU38486 had no effect on net protein catabolism that could be specifically attributed to uremia, the demonstrated anticatabolic effectiveness in a stress accentuated metabolic situation should be studied more closely. Possible targets for therapeutic application under this aspect include post- traumatic states and severe illness.
Professor Martin Schwenen, Düsseldorf, helped with the experimental design, the surgery and was always available for discussion. He has the author's heartfelt gratitude for his generous support.
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