Contribution of the transcription factor Nrf2 for the vascular alterations associated with arterial hypertension induced by aldosterone

Abstract

Aldosterone (Aldo), synthesized mainly in the glomerular zone of the adrenal tissue, but also in extra-renal tissues such as the central nervous system and the cardiovascular system, is a mineralocorticoid (MR) receptor agonist. Aldo's main function is the regulation of the hydroelectrolytic balance, by increasing the reabsorption of the sodium ion (Na+), decreasing plasma concentrations of potassium (K+) and by activation of the renin-angiotensin system. In the cardiovascular system Aldo favors the generation of reactive oxygen species (ROS) via activation of the NAD(P)H oxidase enzyme. ROS contribute to vascular dysfunction by reducing the bioavailability of nitric oxide in endothelial cells and, consequently, increasing the contractile tone of the vascular smooth muscle cells. Various cell types developed adaptive programs to neutralize oxidative stress. The erythroid nuclear factor 2 related to factor 2 (Nrf2), for example, recruits the transcriptional machinery to promote expression of various antioxidant proteins. The transcriptional activity of Nrf2 is finely regulated by repressor proteins, including Keap-1 and the nuclear Bach-1, proteins that inhibit its activity. Considering that Aldo is a potent inducer of ROS and that Nrf2 is a redox-sensitive transcription factor that activates transcription of antioxidant genes, we hypothesized that Aldo negatively regulates the antioxidant system Nrf2, via increased expression of Keap-1 and Bach-1, favoring the accumulation of ROS and subsequent vascular dysfunction (AU)