Paracrine and Intracrine Angiotensin 1-7/Mas Receptor Axis in the Substantia Nigra of Rodents, Monkeys, and Humans

In addition to the classical hormonal (tissue-to-tissue) renin-angiotensin system (RAS), there are a paracrine (cell-to-cell) and an intracrine (intracellular/nuclear) RAS. A local paracrine brain RAS has been associated with several brain disorders, including Parkinson's disease (PD). Classically, angiotensin II (Ang II) is the main RAS effector peptide and acts through two major receptors: Ang II type 1 and 2 (AT1 and AT2) receptors. It has been shown that enhanced activation of the Ang II/AT1 axis exacerbates dopaminergic cell death. Several new components of the RAS have more recently been discovered. However, the role of new Ang 1-7/Mas receptor RAS component was not investigated in the brain and particularly in the dopaminergic system. In the present study, we observed Mas receptor labeling in dopaminergic neurons and glial cells in rat mesencephalic primary cultures; substantia nigra of rats, monkeys, and humans; and human induced pluripotent stem (iPS) cells derived from healthy controls and sporadic PD patients. The present data support a neuroprotective role of the Ang 1-7/Mas receptor axis in the dopaminergic system. We observed that this axis is downregulated with aging, which may contribute to the aging-related vulnerability to neurodegeneration. We have also identified an intracellular Ang 1-7/Mas axis that modulates mitochondrial and nuclear levels of superoxide. The present data suggest that nuclear RAS receptors regulate the adequate balance between the detrimental and the protective arms of the cell RAS. The results further support that the brain RAS should be taken into account for the design of new therapeutic strategies for PD.