Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Abstract

It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra- or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra- and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptors (AT2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.

Keywords: angiotensin; barin; blood pressure; fluid; renin.

Fig. 1.

Neural circuitry: efferent projections from the SFO. The core of the subfornical organ (SFO) is highly vascularized and lacks a blood-brain barrier (BBB). Efferent projections (in red) from this region include those affecting sympathetic nerve activity (SNA) directly though projections to sympathetic neurons of the parvocellular PVN (pPVN) or indirectly through projecting to cells of the pPVN that project to sympathetic neurons of the rostroventral lateral medulla (RVLM). The periphery of the SFO can be affected by factors within the cerebrospinal fluid (CSF). Among its projections (in blue) are those regulating the vasopressin (AVP) axis through the supraoptic nucleus (SON) and magnocellular PVN (mPVN, blue). Projections (in yellow) are also sent to the median preoptic nucleus (MnPO). The cartoon is designed to illustrate the neural connections from the SFO but not their actual path.

Fig. 2.

Schematic of mouse models. The figure schematically illustrates the sRA^Flox and sRA^Red models described in the text. Brain-specific production of ANG II occurs in the double transgenic sRA^Flox mice in and around cells expressing human renin under the control of a neuron-specific promoter and human angiotensinogen under the control of its own promoter (which is active in glial cells and certain neurons). These mice exhibit robust polydipsia, hypertension, and elevated resting metabolic rate. Expression of human angiotensinogen can be ablated in response to cre-recombinase. This cell-specific ablation can occur by breeding with an appropriate cre-driver or by injection of a virus expressing cre-recombinase. After SFO-targeted delivery of Cre-recombinase, the sRA^Flox mice exhibited attenuated drinking and blood pressure. As an alternative, production of ANG II will only occur in response to cre-mediated recombination in the sRA^RED mouse model. This is because production of human angiotensinogen is blocked by a “STOP” signal that can be removed by cre-recombinase. Thus sRA^RED mice exhibit no changes in phenotype in the absence of a cre-driver. After SFO-targeted delivery of Cre-recombinase, the sRA^RED mice exhibited increased water and sodium intake and increased salt preference.