This study for the first time shows oxidative stress mediated genotoxic effects of AngII in vivo. Furthermore, the increase of 8-oxodG suggests a mutagenic potential of an activated renin-angiotensin-aldosterone system, which is often found in hypertensive patients.

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IntroductionRecently, 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.MethodsIn 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.ResultsAdministration 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.ConclusionAngiotensin 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.

SUMMARY1. A study has been made of Na movements in human red blood cells in order to test their sensitivity to inhibition by furosemide or bumetanide. Net changes as well as influx and efflux were measured.2. Unidirectional Na influx and efflux values confirmed previous evidence for components of both these fluxes sensitive to inhibition by furosemide or bumetanide.3. The difference between furosemide-sensitive unidirectional influx and efflux was determined at [Na]0 140 mm and shown to be non-significant, even when [Na]i was raised to about 45 ,imol ml cells-'. 4. No evidence was found for an influence of furosemide on net movements of Na in cells of either slightly elevated or physiological [Na]1 incubated in a 140 mM-Na medium over 4 h. Incubation of cells, under similar conditions, for 12 h did not reveal a bumetanide-sensitive net Na movement.5. The results suggest that cells with normal or slightly elevated [Na]i, incubated in media of physiological Na concentration, do not possess a mechanism sensitive to inhibition by the loop diuretics that operates to regulate cell Na.