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

Begoña Villar-Cheda,Rita Valenzuela,Miguel Melendez-Ferro,Maria A Costa-Besada,Emma Perez-Costas,Jose L Labandeira-Garcia

doi:10.1038/cddis.2017.439

Abstract

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/H2O2 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-1α 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.

Highlights

The ‘classical’ renin–angiotensin system (RAS) is a circulating humoral system that controls blood pressure
Our previous immunohistochemical and laser confocal microscopy studies have revealed immunolabeling for AT1, AT2 receptors and angiotensinogen in the nuclei of substantia nigra pars compacta (SNc) dopaminergic neurons and MES 23.5 dopaminergic neuron cell line.[5]
We observed that activation of nuclear AT1 receptors by intracellular angiotensin II (AII) triggers a number of mechanisms that may protect cells against oxidative stress

Summary

Introduction

The ‘classical’ renin–angiotensin system (RAS) is a circulating humoral system that controls blood pressure. AT1 receptors mediate major effects of the system, and it is generally considered that protective AT2 receptors antagonize the pro-oxidative effects of AT1 receptors.[1] More recently, local or tissue RAS has been identified in a variety of tissues, including the central nervous system.[2] It is known that the local brain RAS is involved in different brain functions, and appears to be altered in some disorders.[3,4] In previous studies, we have demonstrated the presence of a local RAS in the substantia nigra pars compacta (SNc) and striatum of rodents and primates, including humans.[5,6,7] This local RAS modulates dopamine release[8,9] possibly via mutual regulation between dopamine and angiotensin receptors.[10,11,12] Dysregulation of these interactions exacerbates neuroinflammation, oxidative stress and dopaminergic neuron death.[13,14] In addition, immunohistochemical studies have revealed an apparent intracellular localization of several RAS components in different types of cells, including dopaminergic neurons and glial cells of mammals, including non-human primates and human.[5,15,16] the role of the intracellular RAS, and the nuclear components of the RAS, is still unknown. Our results show that nuclear angiotensin receptors control key events for nuclear–mitochondrial interaction and neuronal survival

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Results

Discussion

Conclusion