Brain Angiotensin Type-1 and Type-2 Receptors in Physiological and Hypertensive Conditions: Focus on Neuroinflammation

Abstract

Purpose of review: To review recent data that suggest opposing effects of brain angiotensin type-1 (AT₁R) and type-2 (AT₂R) receptors on blood pressure (BP). Here, we discuss recent studies that suggest pro-hypertensive and pro-inflammatory actions of AT₁R and anti-hypertensive and anti-inflammatory actions of AT₂R. Further, we propose mechanisms for the interplay between brain angiotensin receptors and neuroinflammation in hypertension.

Recent findings: The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular physiology. This includes brain AT₁R and AT₂R, both of which are expressed in or adjacent to brain regions that control BP. Activation of AT₁R within those brain regions mediate increases in BP and cause neuroinflammation, which augments the BP increase in hypertension. The fact that AT₁R and AT₂R have opposing actions on BP suggests that AT₁R and AT₂R may have similar opposing actions on neuroinflammation. However, the mechanisms by which brain AT₁R and AT₂R mediate neuroinflammatory responses remain unclear. The interplay between brain angiotensin receptor subtypes and neuroinflammation exacerbates or protects against hypertension.

Keywords: AT1R; AT2R; Brain angiotensin receptors; Hypertension; Microglia; Neuroinflammation.

Figure 1.. The inflammatory role of brain angiotensin receptors.

A schematic diagram depicting the pro-inflammatory and anti-inflammatory effects of AT₁R of AT₂R respectively. (a) Angiotensin II acting on AT₁R expressing neuron (red) mediates the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines (CCL2). Pro-inflammatory cytokines activate microglia, and chemokines facilitate immune cell infiltration (macrophages and T-lymphocytes). Activated microglia and infiltrated immune cells further upregulate the expression of pro-inflammatory cytokines. Pro-inflammatory cytokines can further activate neurons, microglia, and recruit immune cells. This establishes a pro-inflammatory state, which together with the sympatho-excitatory actions of AT₁R, increase sympathetic nerve activity (SNA) and blood pressure. (b) Angiotensin II acting on AT₂R expressing neuron (green) mediates the release of anti-inflammatory cytokines (IL-10), which inhibits microglia activation, the recruitment of immune cells and the production of pro-inflammatory cytokines. The anti-inflammatory and the sympatho-inhibitory actions of AT₂R decrease SNA and blood pressure. Pointy head arrow; activation, flat head arrows; inhibition, AP; Area Postrema, MnPO; Median Preoptic Nucleus, NTS; Nucleus of the Solitary Tract, OVLT; Organum Vasculum of the Lamina Terminalis, PVN; Paraventricular Nucleus of the Hypothalamus, SFO; Subfornical Organ.