Brain AGT

The brain RAS has received much attention recently because accumulated experimental evidence has shown its involvement in the development of different forms of hypertension (33). The central action of ANG II is known to regulate several activities that can affect blood pressure, including sympathetic nervous function, vasopressin release, drinking behavior, and the appetite for salt. The expression of AGT is widely distributed throughout the brain, with high expression in those areas involved in cardiovascular regulation, such as the hypothalamus and preoptic areas (34). Renin is also thought to be expressed in the brain and appears localized primarily in neurons but also in some glia (35,36), although this is controversial. To experimentally dissect the role of AGT produced in the brain we developed transgenic mice models that express hAGT in the brain, driven by different promoters. Given that astrocytes are considered as the major source of brain AGT (37), we first generated transgenic mice that express hAGT under the control of the glial-specific, glial fibrillary acidic protein (GFAP) promoter (38). In these mice, hAGT protein was mainly localized in astrocytes, but was also present in neurons in the subfornical organ. Measurement of circulating hAGT has shown that plasma levels of hAGT protein were not elevated over baseline. Direct administration of human renin in the cerebral ventricles of these transgenic mice caused a dose-dependent increase in blood pressure, which was prevented by pretreatment with an AT1 receptor blocker. Furthermore, crossing the GFAP-hAGT mice with mice that express human renin sys-temically led to the development of mice that exhibited moderate, but chronic elevation in blood pressure (about 15 mmHg). In further studies we found that when these double-transgenic mice were provided a choice between tap water and saline, they exhibited a significantly greater preference for saline, because they drink nearly 40% of their total volume as saline as compared with 26% in control mice. To ascertain that the phenotype observed in these double-transgenic mice is a result of the ANG II produced locally in the brain, we crossed the GFAP-hAGT mice with transgenic mice that express human renin under the control of this GFAP promoter (39). The double-transgenic animals had an increase in blood pressure, drinking volume, and salt intake, which indicates that these alterations are caused by the local production and action of ANG II in the central nervous system. All together, these data demonstrate that the AGT produced by astrocytes plays a major role in blood pressure regulation and fluid homeostasis. Other models using antisense techniques to reduce glial AGT similarly support its importance in blood pressure regulation (40), although this is beyond the scope of this chapter. Interestingly, and perhaps surprisingly, glial-specific expression of ANG II was reported to correct the renal defects observed in AGT knockout mice (41).

Because both in vitro and in vivo studies have shown that neurons also produce AGT, which is in accordance with the status of ANG II as a neurotransmitter, we developed mice that express AGT driven by synapsin I (SYN I), a neuron-specific promoter (42). In these transgenic mice, the hAGT protein was detected exclusively in neurons. However, the widespread expression of hAGT throughout the central nervous system that was observed in these animals does not follow the pattern normally exhibited by AGT. This is an experimental limitation resulting from the absence of an appropriate promoter that would allow us to specifically target only those neurons normally expressing AGT, such as the subfornical organ. The hAGT produced in the brain is active as demonstrated by the dose-dependent response of blood pressure to central injection of purified human renin in these transgenic mice. A moderate chronic hypertension and increased drinking intake and salt preference were obtained when these SYN I-hAGT mice were bred with mice that express the human renin driven by the same promoter (39). These findings indicate that neural-derived AGT can be converted locally to ANG II, acting as an autocrine and/or paracrine effector to alter blood pressure and the equilibrium of fluid and electrolytes. Although similar phenotypes regarding cardiovascular function and fluid-electrolyte homeostasis were obtained in both of our transgenic models (whether the expression of hAGT is driven by GFAP or SYN), further studies are required to examine the consequences of differential expression of hAGT on several other functions in which brain RAS is involved, such as cognition, memory, pain perception, sexual behavior, and stress. Models expressing AT-1 receptors in the brain driven by the rat neuron-specific enolase promoter have also been recently reported (43).

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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