Brand Susanne, Amann Kerstin, Mandel Philipp, Zimnol Anna, Schupp Nicole
Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany.
PLoS One. 2014 Dec 31;9(12):e115715. doi: 10.1371/journal.pone.0115715. eCollection 2014.
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.
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.
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.
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.
最近，我们发现血管紧张素II，即调节血压的肾素-血管紧张素-醛固酮系统的活性肽，可导致高血压小鼠的肾脏和心脏中活性氧的形成及DNA损伤。为了一方面进一步研究血管紧张素II引起DNA损伤的机制，另一方面研究针对终末器官损伤的可能干预策略，我们研究了干扰肾素-血管紧张素-醛固酮系统的物质对血管紧张素II诱导的基因组损伤的影响。
在C57BL/6小鼠中，通过输注600 ng/kg•min的血管紧张素II诱导高血压。动物还接受血管紧张素II 1型受体阻滞剂坎地沙坦、盐皮质激素受体阻滞剂依普利酮和抗氧化剂Tempol治疗。通过免疫组织化学和蛋白质表达分析研究DNA损伤和转录因子的激活情况。
给予血管紧张素II导致血压显著升高，仅坎地沙坦可使其降低。在接受血管紧张素II治疗的动物的肾脏和心脏中，可检测到显著的氧化应激（比对照组高1.5倍）。血管紧张素II治疗可使肾脏中对氧化还原敏感的转录因子Nrf2和NF-κB激活（分别比对照组高4倍和3倍），而所有干预措施均可使其降低。在肾脏和心脏中发现DNA损伤增加（分别比对照组高3倍和2倍）以及DNA修复增加（比对照组高3倍）。所有干预措施均可改善这两个器官中的这些效应。一致地，坎地沙坦和Tempol比依普利酮更有效。
血管紧张素II诱导的DNA损伤是由血管紧张素II 1型受体介导的体内氧化应激形成所致。血管紧张素II介导的醛固酮生理性增加会加重DNA损伤作用。因此，阻断血管紧张素II和盐皮质激素受体对终末器官损伤具有有益作用，且与血压正常化无关。
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