Hypertension is associated with an increased cancer mortality and a higher kidney cancer risk. Blood pressure regulating hormones, such as the peptide hormone angiotensin II (AngII), are elevated in hypertension. AngII showed DNA-damaging effects in vitro and in the ex-vivo perfused mouse kidney. Here, the effect of rising doses of AngII was analysed for their genotoxic effects in vivo.
In C57BL/6-mice equipped with osmotic mini pumps, delivering AngII in four different concentrations between 60 ng/kg per min and 1 μg/kg per min during 28 days, the oxidative and DNA damaging effects of AngII were studied, using immunohistochemistry and mass spectrometry.
AngII increased the SBP for up to 38 mmHg over control and adversely affected the kidney function of the mice. In the heart, at the highest dose administered, a significant increase of reactive oxygen species formation (1.4-fold over control) and double-strand breaks could be detected (13-fold over control). In the kidney, a dose-dependent increase of superoxide formation (up to 1.7-fold over control), double-strand breaks (up to 4.7-fold over control) and the mutagenic DNA base modification 7,8-dihydro-8-oxo-guanine (8-oxodG, up to 3.6-fold over control) was observed. Adverse effects already appeared at lower AngII doses, which did not raise the blood pressure. Administration of the radical scavenger tempol significantly decreased oxidative stress (by 20%) in the kidney and DNA double-strand breaks in the kidney by 60% and in the heart by 52%, without being able to lower the blood pressure.
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.
aInstitute of Pharmacology and Toxicology, University of Würzburg, Würzburg
bDepartment of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany
Correspondence to Dr Nicole Schupp, Institute of Pharmacology and Toxicology, Versbacher Strasse 9, 97078 Würzburg, Germany. Tel: +49 931 20148722; fax: +49 931 20148446; e-mail: firstname.lastname@example.org
Abbreviations: γ-H2AX, phosphorylated histone H2AX; 8-oxodG, 7,8-dihydro-8-oxo-guanine; AngII, angiotensin II; ANOVA, analysis of variance; BrdU, 5-bromo-2′-deoxyuridine; DHE, dihydroethidium; GSI, glomerular sclerosis index; MSI, mesangiolysis index; NGAL, neutrophil gelatinase-associated lipocalin; PAS, periodic acid-Schiff stain; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; TSI, tubulointerstitial sclerosis index; VSI, vascular sclerosis index
Received 30 March, 2012
Revised 20 August, 2012
Accepted 18 October, 2012
The study was presented as a conference contribution published in Brand S, Amann K, Schupp N. Angiotensin II causes oxidative stress and DNA damage in mouse kidneys. Naunyn-Schmiedebergs Arch Pharmacol 2011; 383(S1):96.