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 as well as 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.

Figure1

The roles that PRR is proposed to have, in the cardiovascular regulatory centers in the brain to mediate control of BP. PRR is hypothesized to facilitate localized tissue RAS function. 1) By binding and sequestering renin or prorenin in the brain, PRR increases the catalytic efficiency of 2) Agt conversion to Ang I. In this way the PRR is hypothesized to mitigate the limited expression of renin in the brain. 3) Membrane bound ACE, which is expressed in the brain, will then convert Ang I to Ang II in order to 4) stimulate the AT1R.

Figure 2

Downstream signaling by the PRR and role of potential effectors in brain neurons. Top, Activation of PRR by renin or prorenin activates MAP kinases such as ERK 1/2 in the kidney, smooth muscle cells and in brain neurons as well as p38 in the heart. MAP kinase activation by PRR activates TGF-β to promote PAI-1secretion, which leads to fibrosis. In addition PRR stimulates the transcription factor PLZF, which mediates upregulation of the PI3 kinase adaptor protein p85α that promotes PI3-kinase activity. Bottom, Of the potential downstream effector of PRR, in the brain, only ERK 1/2 has been demonstrated, thus far. ERK 1/2, itself mediates gene regulation that include upregulation of enzymes and transporter proteins that promote norepinephrine turnover. ERK 1/2 is also found to modulate K⁺ channel function. Future studies may show that PRR is linked PLZF function to mediate neuronal maturation in the brain. PLZF is present in various regions of the brain where it is important for neuronal organization. PI3-kinase function, linked to PLZF action can further link PRR to channel regulation, in addition, promoting neurite growth. These actions are linked to tissue hypertrophy and end organ failure and also mediate neurogenic hypertension. Black Arrows, established signal transduction pathways; red arrow, inhibitory pathways; dotted lines, candidate pathways.