A current view of brain renin–angiotensin system: Is the (pro)renin receptor the missing link?

Abstract

The renin angiotensin system (RAS) plays a central role in the brain to regulate blood pressure (BP). This role includes the modulation of sympathetic nerve activity (SNA) that regulates vascular tone, the regulation of secretion of neurohormones that have a critical role in electrolyte and fluid homeostasis, and by influencing behavioral processes to increase salt and water intake. Based on decades of research it is clear that angiotensin II (Ang II), the major bioactive product of the RAS, mediates these actions largely via its Ang II type 1 receptor (AT1R), located within hypothalamic and brainstem control centers. However, the mechanisms of brain RAS function have been questioned, due in large part to low expression levels of the rate limiting enzyme renin within the central nervous system. Tissue localized RAS has been observed in heart, kidney tubules and vascular cells. Studies have also given rise to the hypothesis for localized RAS function within the brain, so that Ang II can act in a paracrine manner to influence neuronal activity. The recently discovered (pro)renin receptor (PRR) may be key in this mechanism as it serves to sequester renin and prorenin for localized RAS activity. Thus, the PRR can potentially mitigate the low levels of renin expression in the brain to propagate Ang II action. In this review we examine the regulation, expression and functional properties of the various RAS components in the brain with particular focus on the different roles that PRR may have in BP regulation and hypertension.

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

“…The central nervous system plays a critical role in the long-term regulation of ABP in both health and disease states through alterations in sympathetic outflow (9,14). Increased sympathetic outflow is implicated in the etiology of hypertension.…”

Association of the Novel Non-AT1, Non-AT2 Angiotensin Binding Site with Neuronal Cell Death

“…The brain renin-angiotensin system (RAS) is one of the independently regulated, local angiotensin systems most known for its role in cardiovascular and hydromineral balance regulation in both health and disease (McKinley et al, 2003;Cuadra et al, 2010). Although substantial progress in understanding these functions of the brain RAS has been made, many questions remain unanswered regarding the precise nature and role of the system (Saavedra, 2005;Karamyan and Speth, 2007a;Phillips and de Oliveira, 2008;Speth and Karamyan, 2008).…”

Intranasal Angiotensin II in Humans Reduces Blood Pressure When Angiotensin II Type 1 Receptors Are Blocked

“…With this limited renin availability, ANGII production is compartmentalized within specific nuclei. 5 Intranasally administered ANGII, as well as brain ANGII, may act in a paracrine manner to influence neuronal activity of centers involved in blood pressure regulation. 6,36 Hence, the function of ANGII and its degradation products seems to depend on the compartment of its action.…”

“…Besides its systemic effects on the blood vessels and different organ systems, local ANGII is crucially involved in the central nervous regulation of blood pressure. [1][2][3][4][5][6] ANGII receptors, mainly type 1 receptors (AT1) and also type 2 receptors (AT2), are expressed in several cerebral nuclei where they mediate effects of locally produced ANGII. [7][8][9][10] Inhibition of central nervous ANGII synthesis reversed hypertension in spontaneously hypertensive rats.…”