Glia- and Neuron-specific Expression of the Renin-Angiotensin System in Brain Alters Blood Pressure, Water Intake, and Salt Preference

Abstract

The purpose of this study is to examine the regulation of blood pressure and fluid and electrolyte homeostasis in mice overexpressing angiotensin II (Ang-II) in the brain and to determine whether there are significant physiologic differences in Ang-II production in neurons or glia. Therefore, we generated and characterized transgenic mice overexpressing human renin (hREN) under the control of the glial fibrillary acidic protein (GFAP) promoter (GFAP-hREN) and synapsin-I promoter (SYN-hREN) and bred them with mice expressing human angiotensinogen (hAGT) under the control of the same promoters (GFAP-hAGT and SYN-hAGT). Both GFAP-hREN and SYN-hREN mice exhibited the highest hREN mRNA expression in the brain and had undetectable levels of hREN protein in the systemic circulation. In the brain of GFAP-hREN and SYN-hREN mice, hREN protein was observed almost exclusively in astrocytes and neurons, respectively. Transgenic mice overexpressing both hREN and hAGT transgenes in either glia or neurons were moderately hypertensive. In the gliatargeted mice, blood pressure could be corrected by intracerebroventricular injection of the Ang-II type 1 receptor antagonist losartan, and intravenous injection of a ganglion blocking agent, but not an arginine vasopressin V1 receptor antagonist, lowered blood pressure. These data suggest that stimulation of Ang-II type 1 receptors in the brain by Ang-II derived from local synthesis of renin and angiotensinogen can cause an elevation in blood pressure via a mechanism involving enhanced sympathetic outflow. Glia-and neuron-targeted mice also exhibited an increase in drinking volume and salt preference, suggesting that chronic overexpression of renin and angiotensinogen locally in the brain can result in hypertension and alterations in fluid homeostasis. The peptide angiotensin II (Ang-II)1 is the main circulating effector hormone of the renin-angiotensin system (RAS) and is able to act not only on peripheral vascular structures but also on the central nervous system (CNS) to increase blood pressure (BP) (1). Substantial evidence has accumulated that Ang-II has actions on the CNS including increasing sympathetic outflow, arginine vasopressin (AVP) release, water intake, and salt appetite (2). Existence of a local RAS in the CNS has been suggested, since all components of this system have been reported in the brain. In addition, several lines of evidence point to a contribution of an overactive brain RAS to the hypertensive state in spontaneously hypertensive rats, deoxycorticosterone acetate (DOCA) salt hypertensive rats, Dahl salt sensitive rats, and renal hypertensive rats (3-6).Despite numerous studies demonstrating the important cardiovascular effects of Ang-II or Ang-II receptor antagonists injected into the brain, it remains unclear whether RAS components synthesized in the brain, in particular renin and angiotensinogen (AGT), have an important role in the local synthesis of Ang-II. In the brain, AGT expression is localized mainly in astrocytes (glia) (7,8). To determine whether l...

Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II

“…Consistent with this are reports that ANG II exists in nerve terminals and glial cell populations (8,21). We previously demonstrated that ANG II produced by either neurons or glial cells is functionally active (28). This was accomplished by generating transgenic mice expressing both human AGT (hAGT) and/or human renin (hREN) driven by either the synapsin-I (SYN) promoter, a neuronal promoter, or the glial fibrillary acidic protein (GFAP) promoter, a glial promoter (27)(28)(29).…”

“…The tissue specificity and cell specificity of expression in those models was previously reported (28,29). To obtain concurrent measurements, we first compared resting BP in G-AII, N-AII, and control mice.…”

“…We previously demonstrated that ANG II produced by either neurons or glial cells is functionally active (28). This was accomplished by generating transgenic mice expressing both human AGT (hAGT) and/or human renin (hREN) driven by either the synapsin-I (SYN) promoter, a neuronal promoter, or the glial fibrillary acidic protein (GFAP) promoter, a glial promoter (27)(28)(29). Baseline AP was modestly increased in both models but did not differ from each other.…”

“…Approximately 25% of the offspring from these breedings were double transgenic, and there was no apparent increased mortality in either of the GRϩ/GAϩ mice (glia-derived angiotensin II mice, herein termed G-AII mice) and SRϩ/SAϩ mice (neuron-derived angiotensin II, mice herein termed N-AII mice). Double transgenic mice were identified by PCR of genomic DNA purified from tail biopsy samples using hREN-and hAGT-specific primers as previously described (28). All mice were fed standard mouse diet (LM-485; Teklad Premier Laboratory Diets) and water ad libitum.…”

“…glia-specific promoter GFAP by breeding heterozygous SYN-hREN transgenic mice with heterozygous SYN-hAGT transgenic mice or heterozygous GFAP-hREN transgenic mice (22) with heterozygous GFAP-hAGT transgenic mice (27)(28)(29). Approximately 25% of the offspring from these breedings were double transgenic, and there was no apparent increased mortality in either of the GRϩ/GAϩ mice (glia-derived angiotensin II mice, herein termed G-AII mice) and SRϩ/SAϩ mice (neuron-derived angiotensin II, mice herein termed N-AII mice).…”