OXIDATIVE DNA DAMAGE INDUCED BY BLOOD PRESSURE-REGULATING HORMONES AND POSSIBLE STRATEGIES FOR PREVENTION

Epidemiological studies found an increased risk for kidney cancer in hypertensive patients, who often exhibit increased levels of the blood pressure regulating hormones angiotensin II (AngII) and/or aldosterone (Ald). AngII and Ald cause oxidative DNA damage in kidney tubule (LLC-PK1) cells and in experimental hypertension. Here we explored possible interventions to prevent the formation of genotoxic lesions, by measuring DNA double strand breaks. Addition of antioxidants like N-acetylcysteine, α-tocopherol or tempol protected LLC-PK1 cells from DNA damage caused by AngII or Ald, and tempol was able to reduce genotoxic effects of the hormones in kidneys of mice and rats. The addition of inhibitors of NADPH oxidase, which is activated by AngII and Ald, also decreased DNA lesions. In vivo, apocynin was protective to some extent in rats. In transgenic mice lacking the Nox2 and Nox4 subunits of NADPH oxidase, respectively, no reduction of oxidative damage could be observed, ruling out important roles of these two components. Fortifying the cellular antioxidative defense by activating the transcription factor Nrf2 was showing the best protective effects in vitro as well as in vivo in Ald-treated rats. One of these substances, sulforaphane, was even able to reduce the elevated blood pressure.