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194 Hypertonie 2011 - Poster Hypertonie 2011 - Poster 195
Nephrologie, Düsseldorf, Germany
Increased vascular-reactivity to angiotensin
(Ang) II in atherosclerotic vessels might contribute
to hypertension. Vasocontraction is highly
regulated by the activity of myosin light chain
kinase and phosphatase. Recent studies indicate
that MAP-kinase p38-activation is involved
in this regulation.
ApoE-KO mice on a high-fat diet show increased
progression of atherosclerosis and increased
in oxidative stress.
12 weeks old apoE-KO and wild type (WT) mice
on western diet were treated via osmotic minipumps
either with saline or Ang-(1-7) (82µg/kg/
hr) for 6 weeks. Vascular reactivity was tested
in the model of isolated perfused kidney. AngII
induced renal pressor response was significantly
increased in apoE-KO compared to WT
mice. Chronic Ang-(1-7) treatment attenuated
AngII induced pressor response in apoE-KO
mice. Pre-treatment with SB203580 (5µmol/L),
a p38-inhibitior, attenuated AngII induced renal
pressor response in apoE-KO but not in WT
mice.
In apoE-KO mice, the phospho-p38 to totalp38
ratio in renal cortex homogenates was
significantly increased compared to WT mice
(2.83±0.48vs.1.00±0.08; p< 0.05,arbitrary units)
and chronic treatment with Ang-(1-7) in apoE-
KO mice restored this ratio almost to WT levels
(1.29±0.19vs.2.83±0.48; p< 0.05,arbitrary units).
P38-activity in pre-glomerular vessel was similarly
regulated. In addition, MLC(20) activity was
restored to WT levels after Ang-(1-7) treatment.
In apoE-KO mice, expression of the NADPHoxidase-subunit
p47phox is 1.5-fold increased
and restored by Ang-(1-7) treatment compared
to WT mice. Concordantly, isoprostane-8 excretion,
a marker for oxidative stress, was significantly
reduced in Ang-(1-7) treated apoE-KO mice in
24h-urine.
The presented data demonstrates the involvement
of p38 on AngII induced renal vascular reactivity
in the presented mouse model. Chronic
Ang-(1-7) treatment seems attenuate this effect
by decreasing p38-activity. However, it remains
unclear whether p38-regulation is directly influenced
by MAS-receptor-signaling or if it is
related to Ang-(1-7) induced reduction of oxidative
stress which can influence p38-activity.
Further studies are necessary to elucidate the
underlying mechanism.
PS 72
Aldosterone Causes Oxidative Stress and
DNA Damage in vivo via the Mineraolcorticoid
Receptor and Independent of Blood Pressure
Schupp N. 1 , Amann K. 2 , Queisser N. 3
1Universität Würzburg, Institut für Toxikologie,
Würzburg, Germany, 2Universität Erlangen-
Nürnberg, Pathologie, Erlangen, Germany,
3Universität Würzburg, Würzburg, Germany
An inappropriate increase of the mineralocorticoid
aldosterone (Ald) is often detected in
hypertension. Epidemiological studies found a
higher cancer mortality and an increased risk
to develop kidney cancer in hypertensive individuals.
We recently showed in kidney tubule
cells oxidative and genotoxic effects of Ald and
activation of the transcription factor NF-kB.
The present study investigated the capacity
of aldosterone to induce oxidative/nitrosative
stress, DNA damage and the activation of NFkB
in vivo in rat kidneys.
Sprague-Dawleyratsweretreatedforfourweeks
with Ald and salt to induce a mineralo-corticoid-dependent
hypertension. Ald/salt treat-
ment increased the blood pressure, which was
lowered by tempol, an antioxidant, and hydralazine,
a vasodilator, but not by the mineralocorticoid
receptor (MR) antagonist spironolactone,
administered in a subtherapeutical dose.
Ald/salt treatment caused oxidative stress,
evaluated with dihydroethidium, structural DNA
damage, determined in the comet assay, double
strand breaks, nitric oxide/peroxynitrite production
and NF-kB activation, detected immunhistochemically.
Spironolactone and tempol
decreased all these markers significantly,
while hydralazine had no effect. Ald/salt-treated
kidneys showed a tendency to less apoptosis
and to increased cell proliferation.
This study for the first time shows blood pressure-independent
oxidative and genotoxic effects
of Ald in vivo. Crucial for these effects of Ald is
the MR and the production of ROS. Long-term
activation of NF-kB by persistently high Ald levels
could support resistance to apoptosis and the
survival of damaged cells, and increase cell
proliferation. These actions could contribute to
the increased cancer incidence in hypertension
by initiating carcinogenesis.