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*
Department of Pathology, University of Heidelberg, Germany
Department of Pathology, University of
Erlangen-Nürnberg, Germany
Department of Internal Medicine, University of Heidelberg,
Germany
§
Department of Internal Medicine IV, University of Freiburg,
Germany
||
Solvay Pharma, Hannover, Germany
¶
Department of Internal Medicine, Erasmus University, Rotterdam, The
Netherlands
#
Department of Physiology, University of Hamburg, Germany
**
Department of Pathology, Darmstadt, Germany.
Correspondence to Dr. Kerstin Amann, Dept. of Pathology, University Erlangen-Nürnberg, Krankenhausstrasse 8-10, D-91054 Erlangen, Germany. Phone: +49 09131 85 22291; Fax: +49 09131 85 24745; E-mail: kerstin.amann{at}patho.imed.uni-erlangen.de
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-adreno-receptors is unlikely because an
2-adrenoceptor antagonist increased NE release. At
subantihypertensive doses, moxonidine ameliorates renal structural and
functional damage in SNX animals, possibly through central inhibition of
efferent sympathetic nerve traffic. In kidneys of SNX rats, indirect evidence
was found for increased activity of a reduced number of nerve fibers. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present controlled study was designed: (1) to confirm this observation in another model of renal failure, i.e., the subtotally nephrectomized rat (SNX); and (2) to evaluate potential pathomechanisms. The sympathoplegic agent moxonidine was administered in a dose that did not to lower systemic BP. End points measured included morphologic indices of glomerular, vascular, and tubulointerstitial injury; urinary albumin excretion; and intrarenal content, uptake, and release of norepinephrine (NE).
|
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Group 1 was sham-operated and left untreated, whereas groups 2 and 3 underwent two-step subtotal nephrectomy with removal of 75% (controlled by weighing) of renal cortical tissue of the right kidney (9). Forty-eight hours after the second operation, treatment was started in group 3. Moxonidine was given in food pellets to deliver a daily dose of 1.5 mg/kg body wt. In a pilot study of 4 wk duration, this dose was selected because it caused only very modest lowering of BP in control animals (systolic BP lowering: 1 mg/kg: -0.33%; 2 mg/kg: -2.49%) and no BP lowering in SNX animals. Water and food consumption were measured to control drug intake. Twenty-four-hour BP was measured in four animals per group over the entire 12-wk period using telemetry (see below).
In a separate experiment (study 2), animals (n = 9 to 10 per group) were placed in individual metabolic cages, and 24-h urine collections were performed to measure urine volume and albumin excretion. The kidneys of this repeat experiment were perfused with ice-cold NaCl and used for immunohistology and in situ hybridization (9,10).
Telemetric BP Measurements
Mean arterial pressure, systolic BP, diastolic BP, heart rate (derived from
the peak systolic BP signal, min-1), and motor activity of animals
(U/10 min) were measured by 24-h telemetry (Data Sciences, Inc., St. Paul, MN)
(11).
Urinary Albumin Measurements
Urinary albumin was measured using the microplate technique and a rabbit
anti-rat albumin peroxidase conjugate
(9).
Tissue Preparation
After 12 wk, blood samples were taken and the experiment was terminated by
retrograde perfusion fixation via the abdominal aorta
(9,12).
The kidneys were processed and investigated as described below
(9,12,13,14).
Immunohistochemistry
For staining of the proliferating cell nuclear antigen (PCNA), an anti-PCNA
antibody (Immunotech 1510, Marseille, France) was used in a dilution of 1:150
as described previously in detail
(9,10).
The sections were examined using light microscopy at a magnification of
x 400. The number of PCNA-positive glomerular cells was counted per
glomerular area in 50 systematically subsampled glomeruli
(9). The number of tubular
cells per mm2 tubulointerstitial area was counted on 50
systematically subsampled fields (0.1681 mm2), which were
distributed over all cortical zones.
In Situ Hybridization
To study the effect of moxonidine treatment on transforming growth
factor-ß, renin, and endothelin-1 (ET-1) mRNA expression, nonradioactive
in situ hybridization was performed as described previously in detail
(9). For renin, the sense
primer was 5'-ACCATGAAGGGGGTCTCTCT-3'; the antisense primer was
5'-CTGTGCATACTGGCTCTCCA-3', resulting in a PCR fragment of 296 bp.
For ET-1, the sense primer was 5'-TGGCTTTCCAAGGAGCTCC-3'; the
antisense primer was 5'-GCTTGGCAGAAATTCCAGC-3', resulting in a PCR
fragment of 339 bp.
Indices of Renal Damage
Glomerulosclerosis (as parameter of progression of renal failure in 100
systematically subsampled glomeruli per animal), tubulointerstitial changes
(tubular atrophy, dilation, casts, interstitial inflammation, and fibrosis),
and vascular damage (wall thickening, lumen obliteration, fibrinoid necrosis)
were determined in a blinded manner, using a semiquantitative scoring system
(9). The resulting index in
each animal was expressed as a mean of all scores obtained.
Glomerular Geometry
Paraffin sections were examined by light microscopy, using hematoxylin and
eosin and periodic acid-Schiff stains, at various magnifications. After
determination of kidney weight and volume, the volume densities of cortex,
medulla, and glomeruli were determined using a Zeiss eyepiece (magnifications:
x100 and x400; Integrationsplatte II; Zeiss, Oberkochen, Germany)
and the point counting method (PP = AA
= VV)
(9,12,13,14).
Glomerular number per area (NA) was counted and total
glomerular volume (Vglom) was calculated by multiplying
volume density of glomeruli and cortex volume (VVglom
x VC). Glomerular number per volume (NV)
was determined using the following equation
(13):
 |
Measurement of Intrarenal Angiotensin (AngI and AngII)
Frozen tissue samples (0.4 to 1.2 g) were homogenized in 20 ml of ice-cold
0.1 mol/HCl/80% ethanol as described previously for cardiac tissue
(15) with
125I-labeled angiotensin I (AngI), added before tissue
homogenization, as an internal standard. Homogenates were centrifuged (20,000
x g, 10 min, 4°C), and ethanol in the supernatant was
evaporated (constant air flow); the remainder was diluted (20 ml in 1%
orthophosphoric acid) and centrifuged (20,000 x g). The
supernatant was diluted (equal volume of 1% orthophosphoric acid) and
concentrated on SepPak cartridges (C18+; Waters, Milford, MA). Preparation of
SepPak extracts for HPLC and the HPLC procedure were performed as described
(15). AngI and AngII in the
HPLC fractions were measured by RIA
(16). The average recovery was
70% (results corrected for incomplete recovery).
NE Content, Uptake, and Release
Experimental Design. After decapitation of rats under general
anesthesia, kidneys were removed (control: 1.5 ± 0.2 g wet weight
[gww]; SNX: 1.8 ± 0.1 gww) and 0.3-mm slices of renal cortex were
prepared (control: 24.8 ± 3.0 mg; SNX: 24.8 ± 1.8 mg)
(17). Slices were incubated
with [3H]-NE (0.5 µmol/L, 71.7 Ci/mmol, 60 min) in
Krebs-Henseleit solution bubbled continuously with carbogen (95%
O2, 5% CO2). Slices were transferred into superfusion
chambers between two platinum electrodes and superfused in parallel with
Krebs-Henseleit solution (2 ml/min, 37°C, 20 µmol/L corticosterone, 105
min). After 65 min, cocaine (10 µmol/L) was added. After 80 min, a priming
stimulation (10 Hz, 1 ms, 40 mA, 1 min) was performed and 35 consecutive
samples of the superfusate were collected in 3-min fractions. Four stimulation
periods (S1 to S4; each 5 Hz, 40 mA, 1 ms, 1 min), 6, 33, 60, and 87 min after
start of the collections of superfusate, were performed. Increasing
concentrations of the 2-adrenoceptor antagonist rauwolscine
were added before S2 to S4.
Calculation of Results. Spontaneous outflow of radioactivity from the slices was determined (mean of radioactivity in the superfusate collected during the 3-min collection period immediately before, and 12 min after onset of stimulation). The stimulation induced (S-I) outflow of radioactivity was calculated by subtracting the spontaneous outflow from the radioactivity present in the four 3-min samples collected immediately after the onset of stimulation. The S-I outflow of radioactivity was subsequently expressed as the fraction of total tissue radioactivity at the time of stimulation (fractional S-I outflow of radioactivity). Reference was the release of radioactivity in S1. The fractional S-I outflow of radioactivity of S2 to S4 (fractional release 2 (FR2)-FR4) is expressed as a percentage of that in S1 (FR2-FR4 as percentage of FR1).
Isolated Perfused Kidney Preparation
Rats were anesthetized with sodium pentobarbital (60 mg/kg,
intraperitoneally), and kidneys were isolated and perfused with
Krebs-Henseleit solution (37°C,4.75 ml/min per g tissue)
(18). The perfusion solution
was continuously gassed with carbogen (5% CO2/95% O2)
and passed through a 0.8-µm filter before reaching the kidneys. Bipolar
platinum electrodes were placed around the renal arteries to stimulate the
renal nerves. Perfusion pressure was monitored continuously (Statham P23 Db
pressure transducer; Gould, Oxnard, CA). After preparation, renal nerve
stimulation (RNS) was performed (5 Hz, 30 s, 1 ms, 40 V) to test the viability
of the preparation, followed by a stabilization period (70 min) and two
periods of RNS separated by an interval of 10 min (S1, 1 Hz; S2, 5 Hz). Thirty
minutes after S2, two doses of NE (0.1 and 0.4 µmol/L) were added to the
perfusion line (0.158 µl/min) at an interval of 20 min until the pressor
responses reached a maximum. For determination of the RNS-induced release of
NE, 10 1-min fractions were collected 5 min before each stimulation. Samples
were collected in vials (167 µl of 1 mol/L HCl, 13.3 µl of 0.067 mol/L
ethylenediaminetetra-acetic acid, and 3.3 µl of 1 mol/L
Na2SO4).
Determination of Endogenous NE
The NE in the isolated kidney samples was extracted (adsorption onto
alumina, elution with HClO4). After isolation of NE from cortex
(extraction from 100 mg of cortex with 3 ml of HClO4), NE content
was determined by reversed-phase HPLC detection
(19).
Statistical Analyses
Data are given as mean ± SD. Kruskal-Wallis test or ANOVA was used
for analysis of variance, followed by Duncan multiple range test to determine
whether intergroup differences were significant. The zero hypothesis was
rejected at a level of P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal Data
Weight of left (residual) kidney and 24-h BP were higher after SNX, but
they were not significantly different between untreated and moxonidine-treated
SNX rats. Serum urea concentrations were significantly higher in both SNX
groups compared with controls, and hemoglobin tended to be lower
(Table 1).
|
Morphologic Investigations
The indices of glomerulosclerosis and vascular damage were significantly
lower in moxonidine-treated rats compared with untreated SNX rats
(Table 2). Figure 1C shows the
glomerulosclerosis values of the individual animals. The differences were
significant, as there was no overlap between the groups.
Figure 1, A and B, gives
representative examples of glomerulosclerosis in untreated (Panel A) and
moxonidine-treated SNX rats (Panel B).
|
|
The tubulointerstitial damage index tended to be lower in moxonidine-treated animals, but this did not reach statistical significance. The total number of glomeruli per kidney was lower and the mean glomerular volume was higher after SNX, but values were not significantly different between the two SNX groups.
PCNA Immunohistochemistry
After 12 wk, the number of PCNA-positive glomerular cells (per
mm2 glomerular area) and the number of tubular cells (per
mm2 of tubulointerstitium) were significantly higher in untreated
SNX rats (2.84 ± 1.07 and 5.34 ± 2.14 per mm2)
compared with moxonidine-treated SNX rats (1.63 ± 0.67 and 2.24
± 0.63 per mm2) and controls (1.14 ± 0.9 and 0.8
± 0.35 per mm2) (Figure
2).
|
In Situ Hybridization
As depicted in Figure 3, a
qualitative assessment of transforming growth factor-ß mRNA expression
showed markedly higher expression in untreated SNX rats (Panel A) compared
with moxonidine-treated (Panel B), sham-operated (Panel D), and sense controls
(Panel C). The figure shows representative examples. Qualitatively, expression
of renin and ET-1 mRNA was not different between untreated and
moxonidine-treated SNX rats (data not shown).
|
Urinary Albumin Excretion Rate
Urinary albumin excretion rate at weeks 4, 8, and 12, respectively, was
significantly higher in SNX rats than in controls
(Table 3). From week 8 onward,
values were significantly lower in moxonidine-treated compared with untreated
SNX rats. Figure 4 shows the
individual animal values after 12 wk.
|
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AngII Levels in the Kidney
Renal AngII concentrations per unit wet weight (ww) were significantly
lower in SNX rats, both untreated and moxonidine-treated, compared with
controls. There was no significant difference of AngI or AngII:AngI ratio
between moxonidine-treated and untreated SNX rats (data not shown)
(Figure 5).
|
Sympathetic Innervation of Isolated Kidneys of SNX
To test the integrity of the renal sympathetic system after SNX, the
effects of RNS and NE on renal vascular resistance were tested in isolated
kidneys. After RNS (1 and 5 Hz), pressor responses were 12 ± 1 and 63
± 8 mmHg, respectively. NE (0.1 and 0.4 µmol/L) infusion induced
pressor responses of 30 ± 6 and 102 ± 21 mmHg. RNS (1 and 5 Hz)
induced an NE release of 210 ± 65 and 1470 ± 195 pg/gww,
respectively (Figure 6).
|
[3H]-NE Release and its Modulation by 2-
Adrenoceptors
In the renal cortex, endogenous NE content was reduced after SNX
(Figure 7A), but uptake of
[3H]-NE was similar in both groups
(Figure 7B). The
stimulation-induced fractional release of [3H]-NE from cortex
slices was greater in SNX rats than in controls
(Figure 8A). The
2-adrenoceptor antagonist rauwolscine significantly
increased [3H]-NE release in both groups. The increase was slightly
greater in SNX rats than controls (Figure
8B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several points must be considered when interpreting the results. The number
of animals used for telemetric BP measurements for the entire 12-wk period was
limited for logistical reasons. ß-error calculation shows that the
protocol (four animals per group) had a 90% chance of detecting a 15% BP
difference ( = 0.05). For the morphologic studies, only five control
animals were used since large numbers of control rats in comparable
experiments are available in this laboratory. The control values of the
present experiment are within the established range. As far as the main
comparison (untreated and treated SNX rats) is concerned, the number of 12 and
10 animals per group provided a 90% chance of detecting a 25% difference in
glomerulosclerosis index.
Moxonidine was administered to lower central (20) and potentially peripheral (21) renal sympathetic activity. We acknowledge, however, that moxonidine may also have interacted with imidazoline (I)2 receptors on renal cells (22). Injection of moxonidine into the renal artery or administration in the isolated perfused kidney preparation caused natriuresis (23). Because alternative modes to block sympathetic activity were not used in the present study, the conclusion that moxonidine acted via inhibiting sympathetic tone is plausible, but remains inferential. The dose of moxonidine administered to the rats was high compared with the therapeutic dose in humans. However, it is in line with other animal experiments. In a pilot study, we had verified that this dose did not cause marked systemic BP lowering. This was confirmed by 24-h telemetric BP measurements, so we can exclude confounding changes in systemic BP by moxonidine. We acknowledge, however, that we cannot exclude changes in intrarenal resistances, and thus intrarenal hemodynamic effects.
The study protocol did not address the issue of whether the presumed effects of the sympathetic nervous system were due to direct or indirect actions of catecholamines. For instance, sympathetic stimulation activates the renin system via ß-adrenergic mechanisms (24). Catecholamines and the renin system interact in the kidney also by other mechanisms (25), and the two systems may mutually reinforce each other (26). Nevertheless, the measurements of AngII in residual renal tissue argue against an effect of moxonidine on the intrarenal renin system, but this conclusion must be made cautiously in view of the known compartmentation of renal AngII (27).
Direct effects of catecholamines that may potentially be relevant for renal
damage include proproliferative effects mediated via the ß-adrenoreceptor
(28) that have been documented
in tubular epithelial cells, or influences of catecholamines on the function
of podocytes, key cells in the genesis of glomerular injury
(29). Podocytes express
1- and ß2-adrenoreceptors
(30), and stimulation of
1-adrenoreceptor increases [Ca2+]i,
while stimulation of ß2-adrenoreceptor induces depolarization
via opening of cAMP-dependent Cl- conductance. Apart from changes
in glomerular hydraulic pressure gradient
(31), sympathetic nerve
stimulation and NE application decrease the glomerular diameter
(32), and also
Kf, possibly via contraction of podocyte foot processes
(33). In a previous study
(34), we compared the effect
of the angiotensin-converting enzyme inhibitor ramipril and a high dose of
moxonidine on glomerular morphology in SNX rats. Although glomerulosclerosis
was similarly lowered by both treatments, only ramipril had beneficial effects
on podocyte morphology. Apparently, the agents had different effects on
glomerular cells.
The mechanisms by which pharmacologic reduction of sympathetic activity attenuates progression are unclear. Apart from direct consequences in altered renal hemodynamics, indirect effects, e.g., via reduction in proteinuria (35), must be considered.
Glomerular hyperfiltration may be important for progression of renal failure. Mühlbauer et al. (36) noted that amino acid-induced glomerular hyperfiltration was completely abolished by bilateral renal denervation, suggesting a role of the sympathetic nervous system. Microneurographic studies clearly provided evidence for increased sympathetic nerve activity in patients with terminal and preterminal renal failure (6,26). This has also been confirmed in experimental studies (5,6). Campese and Kogosov documented that the rise in BP after subtotal nephrectomy can be partly prevented by dorsal rhizotomy, i.e., section of the dorsal roots with interruption of excitatory afferent signals (5). Turnover rates of NE in the posterior and lateral hypothalamic region were increased in rats with renal failure (37). Renal afferent nerves project to the hypothalamus running through the dorsolateral aspect of the medulla. Factors potentially involved in the activation of the sympathetic nervous system are complex and may include changes in nitric oxide, ET-1, AngII (26,38,39), and leptin (40). The present observation that NE content and turnover are changed in residual renal tissue is fully consistent with the concept of increased efferent sympathetic nerve traffic.
Because we postulated that increased sympathetic activity was involved in
progression of renal failure, it appeared important to provide at least
indirect information on renal sympathetic nerves in the SNX kidney remnants.
The above hypothesis presupposes that the renal nerves are intact
(41). This point was tested
using the isolated kidney preparation
(18). Stimulation of the renal
nerves at 1 and 5 Hz caused marked NE release and frequency-dependent
increases of vascular resistance, likely due to activation of
1-adrenoceptors by neuronally released NE
(42), although we cannot
exclude that other sympathetic neurotransmitters such as neuropeptide Y (NPY)
and ATP participate (43). The
endogenous NE content of renal cortex was significantly lower in SNX rats than
in controls, but the proportion of non-neuronal tissue is presumably increased
in the kidney remnant. To characterize the renal sympathetic nerves, it was
therefore relevant to investigate NE release. [3H]-NE uptake was
similar in SNX rats and controls, presumably indicating the increased uptake
capacity of SNX rats. The enhanced release of NE by the RNS is compatible with
the notion that the renal sympathetic system is more active in SNX rats than
in controls. NE release from sympathetic nerve endings is regulated via
presynaptic modulatory mechanisms, i.e., autofeedback inhibition
mediated by 2-adrenoceptors
(44,45).
The 2-adrenoceptor antagonist rauwolscine enhanced NE
release in SNX kidney cortex, which indicates that NE activates presynaptic
2-autoreceptors to inhibit its own release in this model of
chronic renal failure. The effect of rauwolscine was even greater in SNX rats
than in controls. Thus, less marked inhibition of NE release by
2-adrenoceptors does not explain enhanced NE release in SNX.
We acknowledge that it may not be appropriate to assume that all sympathetic
effects are mediated via catecholamines (see above). NPY concentrations are
increased in renal failure
(46), and NPY has been shown
to act on the kidney
(43,47).
Fragmentary clinical observations are consistent with an effect of sympathetic activity on progression of renal disease. In patients with type I diabetes and diabetic nephropathy, Weinrauch et al. (48) found that progression of renal dysfunction was predicted by the inability to vary the heart rate in response to the Valsalva maneuver. They concluded that unopposed elevation of sympathetic tone in the face of parasympathetic dysfunction was involved. Furthermore, preliminary studies in microalbuminuric patients with type 1 diabetes (unpublished data) show that despite no change in systemic BP by ambulatory BP measurement, low doses of moxonidine reduced urinary albumin excretion rate. Certainly, such clinical observations and the above experimental data do not allow a full assessment of the impact of sympathetic overactivity on progression in patients with renal disease. But our data suggest that the renin-angiotensin and the endothelin systems (49), as well as sympathetic overactivity, are apparently involved in the pathogenesis of structural and functional changes in the kidney in renal failure. This pathomechanism may provide a novel therapeutic window.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2D-Adrenoceptors modulate renal norepinephrine release in
normotensive and spontaneously hypertensive rats. Eur J
Pharmacol 271:283
-292, 1994[Medline]
-2-adrenoceptors in isolated
perfused kidneys of spontaneously hypertensive rats. Cardiovasc
Res 30: 857-865,1995[Medline]
-Autoreceptor
subclassification in rat isolated kidney by use of short trains of electrical
stimulation. Br J Pharmacol108
: 262-268,1993[Medline]
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