The intracellular angiotensin system buffers deleterious effects of the extracellular paracrine system

• Published in: Cell death & disease 2017-09, Vol.8 (9), p.e3044-e3044
• Main Authors: Villar-Cheda, Begoña, Costa-Besada, Maria A, Valenzuela, Rita, Perez-Costas, Emma, Melendez-Ferro, Miguel, Labandeira-Garcia, Jose L
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/51; 38/91; 631/378/1697; 631/378/340; 631/80/86; 96/35; 96/63; Aging - genetics; Aging - metabolism; Angiotensin; Angiotensin II; Angiotensin II - metabolism; Angiotensin II - pharmacology; Animals; Antibodies; Biochemistry; Blood pressure; Blood Pressure - physiology; Brain; Cell Biology; Cell Culture; Cell Line; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Nucleus - ultrastructure; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - ultrastructure; Gene Expression Regulation; Humans; Hydrogen Peroxide - metabolism; Immunology; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Intracellular; Life Sciences; Male; Mice; Mice, Inbred C57BL; Neurons; Nuclear receptors; Original; original-article; Oxidative stress; Paracrine Communication - physiology; Paracrine signalling; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Primary Cell Culture; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Renin; Renin-Angiotensin System - genetics; Signal transduction; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Substantia Nigra - cytology; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Superoxide; Superoxides - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.439

The ‘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 are commonly 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 RAS counteracts the intracellular superoxide/H 2 O 2 and oxidative stress induced by the extracellular/paracrine angiotensin II acting on plasma membrane receptors. Activation of nuclear receptors by intracellular or internalized angiotensin triggers a number of mechanisms that protect the cell, such as an increase in the levels of protective angiotensin type 2 receptors, intracellular angiotensin, PGC-1 α and IGF-1/SIRT1. Interestingly, this protective mechanism is altered in isolated nuclei from brains of aged animals. The present results indicate that at least in the brain, AT1 receptor blockers acting only on the extracellular or paracrine RAS may offer better protection of cells.