The NADPH Oxidase Isoform 1 Contributes to Angiotensin II-Mediated DNA Damage in the Kidney.

Anna Zimnol,Nora Spicker,Katrin Schröder,Nicole Schupp,Ronja Balhorn

doi:10.3390/antiox9070586

Anna Zimnol, Nora Spicker + Show 3 more

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https://doi.org/10.3390/antiox9070586

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Abstract

In higher concentrations, the blood pressure regulating hormone angiotensin II leads to vasoconstriction, hypertension, and oxidative stress by activating NADPH oxidases which are a major enzymatic source of reactive oxygen species (ROS). With the help of knockout animals, the impact of the three predominant NADPH oxidases present in the kidney, i.e., Nox1, Nox2 and Nox4 on angiotensin II-induced oxidative damage was studied. Male wildtype (WT) C57BL/6 mice, Nox1-, Nox2- and Nox4-deficient mice were equipped with osmotic minipumps, delivering either vehicle (PBS) or angiotensin II, for 28 days. Angiotensin II increased blood pressure and urinary albumin levels significantly in all treated mouse strains. In Nox1 knockout mice these increases were significantly lower than in WT, or Nox2 knockout mice. In WT mice, angiotensin II also raised systemic oxidative stress, ROS formation and DNA lesions in the kidney. A local significantly increased ROS production was also found in Nox2 and Nox4 knockout mice but not in Nox1 knockout mice who further had significantly lower systemic oxidative stress and DNA damage than WT animals. Nox2 and Nox4 knockout mice had increased basal DNA damage, concealing possible angiotensin II-induced increases. In conclusion, in the kidney, Nox1 seemed to play a role in angiotensin II-induced DNA damage.

Highlights

Hypertension increases heart attacks, strokes, and chronic kidney disease
The experiments reported here were conducted in four parts, each with 5–6 wildtype animals in a control and a treatment group additional to the knockout animals listed below, with the Nox4 knockout mice experiments conducted in two subsequent experiments
II seen on the relative kidney weight, the hearts of animals of all angiotensin II-treated groups except for the Nox4 knockout group showed a significant gain of weight

Summary

Introduction

Hypertension increases heart attacks, strokes, and chronic kidney disease. Hypertensive patients exhibit an increased incidence of cancer, especially renal cell cancer, for which hypertension is an established risk factor [1,2,3]. As a prerequisite for cancer development, mutations occur in cells which often arise from DNA damage. As a possible molecular mechanism for the increased cancer risk due to hypertension, we have been studying genotoxic effects of the hormone system that controls blood pressure, the renin angiotensin aldosterone system (RAAS), which is often deregulated in hypertensive patients [4,5]. We have proven that chronic angiotensin II excess leads to permanent mutations in kidney cell DNA of rats [9]

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