Expression of angiotensinogen and receptors for angiotensin and prorenin in the monkey and human substantia nigra: an intracellular renin–angiotensin system in the nigra

Pablo Garrido-Gil,Jose L Lanciego,Begoña Villar-Cheda,Rita Valenzuela,Jose L Labandeira-Garcia

doi:10.1007/s00429-012-0402-9

Abstract

We have previously obtained in rodents a considerable amount of data suggesting a major role for the brain renin–angiotensin system (RAS) in dopaminergic neuron degeneration and potentially in Parkinson’s disease. However, the presence of a local RAS has not been demonstrated in the monkey or the human substantia nigra compacta (SNc). The present study demonstrates the presence of major RAS components in dopaminergic neurons, astrocytes and microglia in both the monkey and the human SNc. Angiotensin type 1 and 2 and renin–prorenin receptors were located at the surface of dopaminergic neurons and glial cells, as expected for a tissular RAS. However, angiotensinogen and receptors for angiotensin and renin–prorenin were also observed at the cytoplasm and nuclear level, which suggests the presence of an intracrine or intracellular RAS in monkey and human SNc. Although astrocytes and microglia were labeled for angiotensin and prorenin receptors in the normal SNc, most glial cells appeared less immunoreactive than the dopaminergic neurons. However, our previous studies in rodent models of PD and studies in other animal models of brain diseases suggest that the RAS activity is significantly upregulated in glial cells in pathological conditions. The present results together with our previous findings in rodents suggest a major role for the nigral RAS in the normal functioning of the dopaminergic neurons, and in the progression of the dopaminergic degeneration.

Highlights

The renin–angiotensin system (RAS) has long been considered as a circulating humoral system that regulates blood pressure and water homeostasis
Angiotensinogen and receptors for angiotensin and renin–prorenin were observed at the cytoplasm and nuclear level, which suggests the presence of an intracrine or intracellular RAS in monkey and human substantia nigra compacta (SNc)
In a series of recent studies (Joglar et al 2009; RodriguezPallares et al 2008; Valenzuela et al 2010), we demonstrated the presence of angiotensin receptors in nigral dopaminergic neurons and glial cells in rodents, as well as in rat primary mesencephalic cultures (Joglar et al 2009; Rodriguez-Pallares et al 2004, 2008)

Summary

Introduction

The renin–angiotensin system (RAS) has long been considered as a circulating humoral system that regulates blood pressure and water homeostasis. It is generally accepted that in addition to the ‘‘classical’’ humoral RAS there exist local RAS in many tissues, including brain tissue (Ganong 1994; Re 2004), and that locally formed AngII regulates processes such as cell growth/apoptosis and inflammation (Ruiz-Ortega et al 2001; Suzuki et al 2003). Emerging aspects of the RAS, such as the identification of a specific receptor for renin and its precursor prorenin (PRR) (Nguyen 2011; Nguyen et al 2002) and the identification of a functional intracellular/intracrine RAS in several types of cells, in addition to the ‘‘classical’’ humoral RAS and the local or tissue RAS (Baker et al 2004; Re 2003), are contributing to a better understanding of the RAS and RAS-related diseases (Kumar et al 2007, 2009)

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Conclusion