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

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.

Dopamine Receptors and Neurodegeneration

“…Furthermore pro-renin receptors were found expressed in the nigral DAergic neurons and microglial cells in humans, monkeys and rats [121,105]. Moreover, the pro-renin, AT1Rs and AT2Rs have been located intracellular compartments in DAergic neurons and glial cells [105]. These observations suggest the existence of an intracellular and intracrine RAS in dopaminergic neurons and functional interaction between DA receptors and AII receptors.…”

“…An important number of studies in peripheral tissues, a direct counter-regulatory interaction between AT1Rs and D2Rs has been also demonstrated [119,120]. Furthermore pro-renin receptors were found expressed in the nigral DAergic neurons and microglial cells in humans, monkeys and rats [121,105]. Moreover, the pro-renin, AT1Rs and AT2Rs have been located intracellular compartments in DAergic neurons and glial cells [105].…”

“…For example, several studies have reported the presence of RAS components in the basal ganglia, particularly in the nigro-striatal system [100,101,102,103]. The AT1Rs and AT2Rs were found to be expressed in primary mesencephalic cell cultures [104,95,96], in nigral DAergic neurons and glial cells in both rodents and primates [105] and it was shown that AII induces DA release, which is blocked by AT1Rs antagonists [106]. The interaction between the RAS and the DAergic system is particularly interesting, previous evidences suggested that DA and angiotensin systems directly counter-regulate each other in renal cells [107] and that abnormal counter-regulatory interactions between dopamine and AII play an important role in renal degeneration and hypertension [108].…”

The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism

“…Nigral DA neurons express various subunits of Nox and nearly all DA neurons express AT1 receptors thus allowing for actions of AngII directly on DA neurons (Garrido, et al, 2013, Grammatopoulos, et al, 2007, Rodriguez-Perez, et al, 2010). In a DA cell line (N27 cells), which expresses Nox, AT1 receptor antagonism reduces MPP+-induced ROS in a manner similar to that seen with pharmacological inhibition or siRNA silencing of Nox providing a functional link between AT1 receptors, Nox activity and DA function (Garrido-Gil, et al, 2012, Rodriguez-Perez, et al, 2012).…”

No Brain Renin–Angiotensin System

“…Indeed, within the past ~5 years, evidence for angiotensinogen and prorenin in the CSF and brain tissue is reported with the potential upregulation in pathological states. 26,27 Thus, absent use of newer or improved, more sensitive methods, in particular the application of acute or chronic molecular interventions and more precise cellular and regional localization techniques, the current study does not provide additional insight over the existing literature to disprove the existence of a local functioning brain RAS.…”