Fig. 2.

Modulation by nuclear angiotensin receptors of the pro-oxidative effects of activation of the plasma membrane AT1-Nox2 axis . Activation of surface AT1 leads to generation of intracellular superoxide/H₂O₂ and oxidative stress (red arrows). However, activation of AT1 also induces internalization of the Ang II-AT1 receptor complex to the nucleus (red arrows). Nuclear AT1 receptor activation leads to an increase in NOX4/superoxide/H₂O₂ and IP3/Ca²⁺ levels that, via regulation of gene expression, trigger several mechanisms that may protect cells against oxidative stress (green arrows): (i) an increase in the levels of protective AT2 receptors that traffic to mitochondria and cell membrane leading to a compensatory upregulation of the RAS protective arm (i.e. AII/AT2); (ii) an increase in the synthesis of intracellular angiotensinogen/AngII to act on intracellular AT2 receptors and, via Ang 1-7, intracellular Mas receptors; (iii) upregulation of mRNA expression for PGC-1α and IGF-1, which, possibly interacting with SIRT1, enhance mitochondrial protection and reduce oxidative damage. Nuclear AT2 and Mas receptors modulate the effects of nuclear AT1 receptors by increasing nuclear levels of NO (blue arrows). Abbreviations: ANG, angiotensinogen; Ang II, angiotensin II; Ang 1-7, angiotensin 1-7; AT1, angiotensin type 1; AT2, angiotensin type 2; IGF-1, insulin-like growth factor 1; IP3R, inositol 1,4,5-trisphosphate receptor; MAS, Mas receptors; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PRR, prorenin/renin receptors; ROS, reactive oxygen species; SIRT1, sirtuin 1. Images were produced using Servier Medical Art (http://www.servier.com).