How Is the Brain Renin–Angiotensin System Regulated?

Abstract

The renin–angiotensin system (RAS) is one of the most studied physiological pathways controlling arterial blood pressure (BP). The longevity of RAS blockers as effective antihypertensive therapies evidences the continued clinical importance of the RAS. New components of the RAS and novel mechanisms continue to be discovered with regularity. For example, the RAS has recently been implicated in metabolic control and its association with metabolic pathways.1–3 Moreover, the RAS is one of the most complex systems because of the interaction between circulating and tissue RAS, among RAS in different tissues, and the activity of counter-regulatory peptides and receptors, vis-a-vis Ang-II/angiotensin type 1 (AT1) receptor versus Ang-(1–7)/Mas. The intricate neural circuitry between cardiovascular, fluid homeostasis, and metabolic control regions, some of which have the capacity for the independent generation and action of angiotensin peptides further complicates our understanding of the brain RAS. Instead of an all-encompassing review of the brain RAS, which can be found elsewhere, this article will focus primarily on investigations into how RAS activity in the brain is regulated.4 There have been numerous studies examining the transcriptional mechanisms regulating expression of the angiotensinogen (AGT) gene. A vast majority of these studies have focused on hepatocytes and renal proximal tubule. In the brain, AGT is expressed in astrocytes and in some neurons, particularly in regions of the brain controlling cardiovascular and metabolic function.5–7 Expression of AGT in glial cells is of clear importance as overexpression of the human RAS in glial cells results in hypertension, and its removal from glia significantly blunts hypertension in mice.8,9 Similarly, transgenic rats with decreased glial AGT exhibit severe defects in water homeostasis and a blunting of hypertension when bred with a rat model of increased brain Ang-II.10 It has been widely presumed that …