Oxidative DNA damage in kidneys and heart of hypertensive mice is prevented by blocking angiotensin II and aldosterone receptors
| Autor: | Philipp Mandel, Anna Zimnol, Kerstin Amann, Susanne Brand, Nicole Schupp |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Angiotensin receptor DNA Repair lcsh:Medicine Tetrazoles Blood Pressure Spironolactone medicine.disease_cause Kidney Biochemistry Vascular Medicine Antioxidants Renin-Angiotensin System Mice Cell Signaling Medizinische Fakultät Medicine and Health Sciences lcsh:Science Aldosterone Mineralocorticoid Receptor Antagonists Multidisciplinary biology Guanosine Chemistry Angiotensin II NF-kappa B Heart 8-Hydroxy-2'-Deoxyguanosine Hypertension DNA modification Research Article Signal Transduction medicine.medical_specialty DNA repair DNA damage NF-E2-Related Factor 2 Cyclic N-Oxides Internal medicine Renin–angiotensin system medicine Genetics Animals ddc:610 Angiotensin II receptor type 1 Biology and life sciences lcsh:R Biphenyl Compounds Deoxyguanosine Angiotensin-converting enzyme DNA Cell Biology Eplerenone Enzyme Activation Mice Inbred C57BL Oxidative Stress Endocrinology biology.protein lcsh:Q Benzimidazoles Spin Labels Transcriptional Signaling Reactive Oxygen Species Angiotensin II Type 1 Receptor Blockers Oxidative stress |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 12, p e115715 (2014) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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