The International Journal of Biochemistry & Cell Biology
ReviewThe brain renin–angiotensin system: location and physiological roles
Introduction
Angiotensin (Ang) II is a neuropeptide with multiple actions on the brain. The distribution of its AT1 receptor in the CNS (Fig. 1) coincides with several cerebral regions known to regulate cardiovascular and body fluid homeostasis (Allen et al., 2000, Lenkei et al., 1997). It is likely that an intrinsic brain renin–angiotensin system (RAS) exists (Bader & Ganten, 2002). However, the exact modus operandi of such a system, and whether it is a network of angiotensinergic neural pathways rather than a brain RAS is still to be clarified.
Neither renin nor Ang peptides pass readily from the blood into the brain interstitium (Fei et al., 1982; Ganten, Hutchinson, Schelling, Ganten, & Fischer, 1976). Therefore, it is necessary to distinguish those cerebral regions that are separated by the blood–brain barrier from the environment of the systemic circulation, from those few regions—the circumventricular organs (CVOs), that lack the blood–brain barrier (McKinley et al., 1990) and are influenced directly by the peripheral RAS. This review focuses on angiotensin’s influence in brain regions with a blood–brain barrier, but its actions on the subfornical organ, OVLT and area postrema (the sensory CVOs) will be briefly considered. Blood-borne Ang II interacts with the brain through AT1 receptors located on neurons in these CVOs and these neurons may project to many other brain regions behind the blood–brain barrier (Giles et al., 1999, McKinley et al., 1990).
Activation of these neural circuits by circulating Ang II acting on the subfornical organ or organum vasculosum laminae terminalis (OVLT) may cause thirst, vasopressin secretion and an appetite for salt (Fitts, Starbuck, & Ruhf, 2000a; Mangiapane, Thrasher, Keil, Simpson, & Ganong, 1984; Menani, Colombari, Beltz, Thunhorst, & Johnson, 1998; Simpson, Epstein, & Camardo, 1978). The main action of circulating Ang II on the area postrema is to increase arterial pressure (Otsuka, Barnes, & Ferrario, 1986). It is possible that some neural pathways activated by Ang action on the CVOs may utilise Ang II or Ang III generated in the brain as transmitter molecules (Lind & Johnson, 1982). It is also probable that high concentrations of angiotensin-converting enzyme (ACE) in the CVOs results in local generation of Ang II within the CVOs (Brownfield, Reid, Ganten, & Ganong, 1982).
Section snippets
Angiotensinogen in the brain
Angiotensinogen is synthesised in most regions of the brain, although some regions e.g. medulla, hypothalamus, predominate over others in this regard (Lynch et al., 1987, Stornetta et al., 1988). It is a constituent of brain extracellular fluid and one of the more abundant proteins found in cerebrospinal fluid (Hilgenfeld, 1984). By far the greatest proportion of angiotensinogen synthesis within the CNS occurs in glial cells (Stornetta et al., 1988; Intebi, Flaxman, Ganong, & Deschepper, 1990).
Renin
Evidence for angiotensin production within the CNS is over 30 years old, although the enzyme responsible was probably cathepsin D (Ganten et al., 1971, Fischer-Ferraro et al., 1971, Reid, 1979). More recent studies show that while mRNA encoding renin is present in the CNS, its concentration is low (Dzau, Ingelfinger, Pratt, & Ellison, 1986), and its spatial relationship to centrally synthesised angiotensinogen is unclear. Recently, transgenic strains of mice in which a large part of the gene
Angiotensin peptides
Ang I, Ang II, Ang III and Ang 1–7 have all been identified in brain tissue, although the latter two are found in very low concentrations (Chappell et al., 1987, Chappell et al., 1989, Lawrence et al., 1992). Immunohistochemical identification of Ang II or Ang III in rat brain reveals that an extensive system of Ang-containing fibres and nerve terminals occur in specific brain regions (Lind et al., 1985, Oldfield et al., 1989). However, neuronal cell bodies exhibiting Ang-like immunoreactivity
Angiotensin receptors
Angiotensin receptors are located in many specific regions of the brain (Fig. 1) and spinal cord (Allen et al., 2000, Lenkei et al., 1997; Mendelsohn et al., 1984, Gehlert et al., 1986, McKinley et al., 1987, Allen et al., 1988a). These receptors are of the AT1, AT2 and AT4 subtypes. AT1 receptors are further subgrouped in the rodent brain into AT1A and AT1B receptors. In regard to AT1 receptors, in vitro autoradiographic binding studies, in situ hybridisation histochemistry, and
AT1 receptors
The highest densities of AT1 receptor binding are usually found on neurons in the lamina terminalis, hypothalamic paraventricular nucleus and the NTS (Allen et al., 2000). Within the lamina terminalis, the subfornical organ and OVLT that are exposed to circulating angiotensins contain AT1 receptors. The other sensory CVO, the area postrema contains a lower density of AT1 receptors, although in humans it appears to lack such receptors (Allen et al., 1988a). The other component of the lamina
AT2 receptors
AT2 receptors have been detected by in vitro autoradiographic techniques using selective AT2 antagonists to displace binding of radiolabelled Ang II peptide analogues such as sarile (Rowe, Grove, Saylor, & Speth, 1990). In the rat, several brain regions exhibit AT2 receptor binding, especially in the molecular layer of the cerebellum and in the thalamus. In situ hybridisation studies show that AT2 receptor mRNA is also expressed in these regions (Lenkei et al., 1997; Millan, Jacobowitz,
AT4 receptors
The AT4 receptor is defined as the high affinity binding site that selectively binds Ang IV with affinity ranging from 1 to 10 nM (Swanson et al., 1992). Ang IV, VYIHPF is produced by the consecutive actions of aminopeptidases A and N on angiotensin II. This hexapeptide was initially thought to be inactive because of its inability to activate the classical angiotensin AT1 and AT2 receptors except at high micromolar concentrations. This peptide has subsequently been shown to elicit dramatic
Arterial pressure
Ang II may influence arterial pressure at any one of a number of brain sites. Micro-injection of Ang II into the lateral or third ventricle, hypothalamic PVN, several forebrain regions, rostral ventrolateral medulla, NTS, the area postrema and subfornical organ increases arterial pressure (Severs and Daniels-Severs, 1973, Jensen et al., 1992, Thornton and Nicolaidis, 1993, Allen et al., 1988b, Andreatta et al., 1988, Averill et al., 1987, Simpson, 1981). The many observations that ICV
Thirst
ICV administration of Ang II or Ang III causes many species to drink relatively large volumes of water within a few minutes (Epstein et al., 1970, Sharpe and Swanson, 1974, Abraham et al., 1975, Fitzsimons and Kucharczyk, 1978). This effect of centrally administered Ang II is abolished by ablation of the AV3V region, but not by ablation of the subfornical organ (Buggy and Johnson, 1978, Lind et al., 1984). Therefore, Ang II infused by the ICV route is unlikely to be acting on the Ang II
Vasopressin secretion
ICV infusion of Ang II is a potent stimulus to the release of vasopressin (Mouw et al., 1971, Andersson et al., 1972, Fyhrquist et al., 1979). This effect is abolished by ablation of the AV3V region (Bealer, Phillips, Johnson, & Schmid, 1979) or prior ICV administration of an AT1 antagonist (Mathai, Evered, & McKinley, 1998). There are efferent neural pathways from the AV3V region to the magnocellular neurons of the supraoptic and paraventricular nuclei (Wilkin, Mitchell, Ganten, & Johnson, 1989
Renal nerves
In the anaesthetised rat, ICV infusion of Ang II increases RSNA (Huang & Leenen, 1996). By contrast, ICV infusion of Ang II in the conscious rat, rabbit or sheep causes a very large and long-lasting depression of RSNA (Kannan et al., 1991, Dorward and Rudd, 1991, May and McAllen, 1997a). This effect was partially independent of the baroreceptor activation, which results from the increase in arterial pressure caused by centrally injected Ang II (Dorward and Rudd, 1991, May and McAllen, 1997a). AT
Regulation of body temperature
Brain Ang is implicated in the regulation of body temperature. Ang II administered centrally reduces core temperature. Both decrease in metabolic heat production (thermogenesis) and an increase in radiated heat contributed to the hypothermic effect of centrally administered Ang II (Lin, 1980; Shido & Nagasaka, 1985). ICV administration of the AT1 antagonist losartan to rats exposed to a hot environment for 1 h appeared to inhibit thermoregulatory cooling mechanisms because there was a much
Adrenocorticotropin secretion
Centrally administered Ang II has been shown to cause stimulation of the hypothalamo-pituitary–adrenal axis, resulting in increased blood levels of adrenocorticotropic hormone (ACTH), and consequently cortisol or corticosterone (Scholkens et al., 1982, Ganong and Murakami, 1987, Sumitomo et al., 1991). This effect is not inhibited by the Ang II antagonist saralasin administered peripherally, indicating that the action of Ang II injected intracerebroventricularly is occurring behind the
Sodium appetite
Centrally injected Ang II or renin are potent stimuli for the ingestion of NaCl in several species (Bryant et al., 1980, Avrith and Fitzsimons, 1980; Coghlan et al., 1981, Fitzsimons, 1998), although the onset is slower than that of Ang-induced water drinking. This action is blocked by centrally administered AT1 or AT2 receptor antagonists (Fitzsimons, 1998; Rowland, Rozelle, Riley, & Fregly, 1992). Further evidence that brain Ang regulates the intake of NaCl comes from experiments showing that
Memory
Central infusions of Ang IV facilitate memory retention and retrieval in rats in passive avoidance paradigms (Braszko et al., 1988, Wright et al., 1993). Moreover, chronic infusions of the more stable analogue of Ang IV, Nle1-Ang IV, improved performance in rats in the spatial learning task, the Morris water maze (Pederson, Harding, & Wright, 1998). In two rat models of memory deficit, induced by either scopolamine or bilateral perforant pathway lesion, the AT4 receptor agonists reversed the
Blood–brain barrier
Mice in which the angiotensinogen gene had been deleted show an impairment in blood–brain barrier function (Kakinuma et al., 1998). This effect does not occur in mice in which the renin gene has been deleted (Yanai et al., 2000). The damage to the blood–brain barrier in angiotensinogen gene knockout mice may be restored by treatment with Ang II or Ang IV. This effect of Ang II or Ang IV is not mediated by either AT1 or AT2 receptors.
Concluding summary
Angiotensinogen, renin and ACE are synthesised within the brain, as are AT1, AT2 or AT4 receptors. Angiotensinogen synthesis occurs predominantly in glia, however how and where it is processed to Ang peptides is unknown. Ang peptides generated within the brain may act on AT1 receptors as neurotransmitters or neuromodulators in neural pathways influencing the cardiovascular system and fluid and electrolyte balance. AT1 receptors mediating these functions are found in the ventrolateral medulla,
Acknowledgements
The authors’ work is supported by NHMRC Institute Block Grant 983001, the J. Robert Jr. and Helen C. Kleberg Foundation, and the G. Harold and Leila Y. Mathers Charitable Foundation.
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