Fig. 3

The intraneuronal RAS compensates (green lines: neuroprotective mechanisms) for the pro-oxidative effects of plasma membrane AT1 receptor activation by paracrine AngII (red lines: pro-neurodegenerative mechanisms). Internalization of the AT1/Ang II complex to the nucleus and activation of nuclear and mitochondrial receptors by intracellular AngII and Ang 1–7, trigger several mechanisms that protect neurons against AT1-induced oxidative stress during normal cell function. Antioxidative AT2, Mas, and MrgE receptors are more abundant in the mitochondria. In the nucleus, activation of AT1 receptors triggers several compensatory mechanisms, including increased mRNA expression of antioxidative RAS receptors, angiotensinogen, IGF1, and PGC1α. However, an excess of cell membrane AngII/AT1 receptor activity to compensate for dopamine decrease or other pathogenic factors may overwhelm the buffering mechanisms, leading to the progression of dopaminergic degeneration. AngII, angiotensin II; Ang1-7, angiotensin 1–7; AT1, angiotensin type 1; AT2, angiotensin type 2; MAS, Mas receptors; MrgE, Mas-related receptor MrgE; Nox4, NADPH-oxidase 4; ROS, reactive oxygen species