Oxidative DNA damage in kidneys and heart of hypertensive mice is prevented by blocking angiotensin II and aldosterone receptors
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Oxidative DNA damage in kidneys and heart of hypertensive mice is prevented by blocking angiotensin II and aldosterone receptors. / Brand, Susanne; Amann, Kerstin; Mandel, Philipp; Zimnol, Anna; Schupp, Nicole.
in: PLOS ONE, Jahrgang 9, Nr. 12, 2014, S. e115715.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Oxidative DNA damage in kidneys and heart of hypertensive mice is prevented by blocking angiotensin II and aldosterone receptors
AU - Brand, Susanne
AU - Amann, Kerstin
AU - Mandel, Philipp
AU - Zimnol, Anna
AU - Schupp, Nicole
PY - 2014
Y1 - 2014
N2 - INTRODUCTION: Recently, we could show that angiotensin II, the reactive peptide of the blood pressure-regulating renin-angiotensin-aldosterone-system, causes the formation of reactive oxygen species and DNA damage in kidneys and hearts of hypertensive mice. To further investigate on the one hand the mechanism of DNA damage caused by angiotensin II, and on the other hand possible intervention strategies against end-organ damage, the effects of substances interfering with the renin-angiotensin-aldosterone-system on angiotensin II-induced genomic damage were studied.METHODS: In C57BL/6-mice, hypertension was induced by infusion of 600 ng/kg • min angiotensin II. The animals were additionally treated with the angiotensin II type 1 receptor blocker candesartan, the mineralocorticoid receptor blocker eplerenone and the antioxidant tempol. DNA damage and the activation of transcription factors were studied by immunohistochemistry and protein expression analysis.RESULTS: Administration of angiotensin II led to a significant increase of blood pressure, decreased only by candesartan. In kidneys and hearts of angiotensin II-treated animals, significant oxidative stress could be detected (1.5-fold over control). The redox-sensitive transcription factors Nrf2 and NF-κB were activated in the kidney by angiotensin II-treatment (4- and 3-fold over control, respectively) and reduced by all interventions. In kidneys and hearts an increase of DNA damage (3- and 2-fold over control, respectively) and of DNA repair (3-fold over control) was found. These effects were ameliorated by all interventions in both organs. Consistently, candesartan and tempol were more effective than eplerenone.CONCLUSION: Angiotensin II-induced DNA damage is caused by angiotensin II type 1 receptor-mediated formation of oxidative stress in vivo. The angiotensin II-mediated physiological increase of aldosterone adds to the DNA-damaging effects. Blocking angiotensin II and mineralocorticoid receptors therefore has beneficial effects on end-organ damage independent of blood pressure normalization.
AB - INTRODUCTION: Recently, we could show that angiotensin II, the reactive peptide of the blood pressure-regulating renin-angiotensin-aldosterone-system, causes the formation of reactive oxygen species and DNA damage in kidneys and hearts of hypertensive mice. To further investigate on the one hand the mechanism of DNA damage caused by angiotensin II, and on the other hand possible intervention strategies against end-organ damage, the effects of substances interfering with the renin-angiotensin-aldosterone-system on angiotensin II-induced genomic damage were studied.METHODS: In C57BL/6-mice, hypertension was induced by infusion of 600 ng/kg • min angiotensin II. The animals were additionally treated with the angiotensin II type 1 receptor blocker candesartan, the mineralocorticoid receptor blocker eplerenone and the antioxidant tempol. DNA damage and the activation of transcription factors were studied by immunohistochemistry and protein expression analysis.RESULTS: Administration of angiotensin II led to a significant increase of blood pressure, decreased only by candesartan. In kidneys and hearts of angiotensin II-treated animals, significant oxidative stress could be detected (1.5-fold over control). The redox-sensitive transcription factors Nrf2 and NF-κB were activated in the kidney by angiotensin II-treatment (4- and 3-fold over control, respectively) and reduced by all interventions. In kidneys and hearts an increase of DNA damage (3- and 2-fold over control, respectively) and of DNA repair (3-fold over control) was found. These effects were ameliorated by all interventions in both organs. Consistently, candesartan and tempol were more effective than eplerenone.CONCLUSION: Angiotensin II-induced DNA damage is caused by angiotensin II type 1 receptor-mediated formation of oxidative stress in vivo. The angiotensin II-mediated physiological increase of aldosterone adds to the DNA-damaging effects. Blocking angiotensin II and mineralocorticoid receptors therefore has beneficial effects on end-organ damage independent of blood pressure normalization.
KW - Aldosterone
KW - Angiotensin II
KW - Angiotensin II Type 1 Receptor Blockers
KW - Animals
KW - Antioxidants
KW - Benzimidazoles
KW - Blood Pressure
KW - Cyclic N-Oxides
KW - DNA Damage
KW - DNA Repair
KW - Deoxyguanosine
KW - Enzyme Activation
KW - Guanosine
KW - Heart
KW - Hypertension
KW - Kidney
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mineralocorticoid Receptor Antagonists
KW - NF-E2-Related Factor 2
KW - NF-kappa B
KW - Oxidative Stress
KW - Reactive Oxygen Species
KW - Renin-Angiotensin System
KW - Spin Labels
KW - Spironolactone
KW - Tetrazoles
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1371/journal.pone.0115715
DO - 10.1371/journal.pone.0115715
M3 - SCORING: Journal article
C2 - 25551569
VL - 9
SP - e115715
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 12
ER -
