Villar Cheda, BegoñaCosta Besada, María AliciaValenzuela Limiñana, RitaPérez Costas, EmmaMeléndez Ferro, MiguelLabandeira García, José Luis2020-07-232020-07-232017Villar-Cheda, B., Costa-Besada, M., Valenzuela, R. et al. The intracellular angiotensin system buffers deleterious effects of the extracellular paracrine system. Cell Death Dis 8, e3044 (2017). https://doi.org/10.1038/cddis.2017.4392041-4889http://hdl.handle.net/10347/23204The‘classical’renin–angiotensin system (RAS) is a circulating system that controls blood pressure. Local/paracrine RAS,identified in a variety of tissues, including the brain, is involved in different functions and diseases, and RAS blockers arecommonly used in clinical practice. A third type of RAS (intracellular/intracrine RAS) has been observed in some types of cells,including neurons. However, its role is still unknown. The present results indicate that in brain cells the intracellular RAScounteracts the intracellular superoxide/H2O2and oxidative stress induced by the extracellular/paracrine angiotensin II acting onplasma membrane receptors. Activation of nuclear receptors by intracellular or internalized angiotensin triggers a number ofmechanisms that protect the cell, such as an increase in the levels of protective angiotensin type 2 receptors, intracellularangiotensin, PGC-1αand IGF-1/SIRT1. Interestingly, this protective mechanism is altered in isolated nuclei from brains of agedanimals. The present results indicate that at least in the brain, AT1 receptor blockers acting only on the extracellular or paracrineRAS may offer better protection of cellseng© The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/http://creativecommons.org/licenses/by/4.0/Extracellular paracrineAngiotensinjournal article10.1038/cddis.2017.439open access