**1.1 Renin-Angiotensin System role on the hydromineral homeostasis**

The Renin-Angiotensin System (RAS) plays an essential role in the maintenance of the hydromineral homeostasis by eliciting sodium and water intake and by inducing sodium urinary retention through aldosterone release and hemodynamic effect via angiotensin II a key component of the RAS [2, 3]. The octapeptide hormone angiotensin II (ANGII) induces its effects on body fluids control mainly by acting on its angiotensinergic receptor type 1 (AT1) [4, 5]. The AT1 receptor is a member of the G-protein (heterotrimeric guanine nucleotide-binding protein) coupled receptor (GPCR) superfamily of integral membrane proteins and is coupled to the Gq. Then, its stimulation leads to the activation of phospholipase C, protein kinase C (PKC), and members of the mitogen-activated protein kinase family (MAPK) as extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 MAPK and c-Jun N-terminal Kinase (JNK) (for review see [6]). Hines et al. [7] showed that the activation of MAPKs, mediated by AT1, can be PKC dependent or independent according to the activated conformations that the receptor may adopt. Recently, some studies have postulated that these intracellular signaling pathways from the AT1 receptor are involved in different ingestive behavioral responses. In this context, ANGII-induced sodium intake requires the PKC-independent ERK1/2 signaling pathway while water intake requires PKC, JNK, and the mechanistic target of the rapamycin complex 1 (mTORC1) signaling pathways [8–10].

ANGII induces rapid and prominent water and sodium intake when injected centrally even in normohydration animals, as well in response to hypovolemic and hyponatremic stimuli [3]. In the brain, peripheral and central ANGII induces sodium and water intake by binding to AT1 in important forebrain structures involved in the generation of fluid intakes, such as the organum vasculosum of the lamina terminalis (OVLT), the median preoptic nucleus (MnPO), and the subfornical organ (SFO) [11, 12]. The SFO is a key sensory circumventricular organ (CVO) involved in the control of body fluids homeostasis, that receives, integrates, and responds to both blood-borne and central nervous system (CNS) signals [5]. The CVOs are specialized structures of CNS, comprising the SFO, area postrema, OVLT, median eminence, and neurohypophysis, which lack the normal blood–brain barrier and thus provide essential communication between the circulation and the CNS [13]. The increase in the circulating and central ANGII levels enhances the neural activity of the SFO, which sends axonal projections to the anteroventral third ventricle region (AV3V), particularly the OVLT and MnPO ventral, and to the hypothalamus as the supraoptic nucleus (SON), and the paraventricular nucleus (PVN) (for review see [5]).

### **1.2 Hypothamalo-neurohypophysial system role on the hydromineral homeostasis**

Magnocellular neurosecretory neurons of the PVN and the SON synthesize vasopressin (AVP) and oxytocin (OT) which are released into the circulation from the neurohypophysis [14]. OT, beyond its classic effects on uterine contraction and myoepithelial cells of the breast alveoli, participates in body fluid control by eliciting natriuresis and sodium appetite inhibition [15–17]. The antidiuretic action of AVP is the main physiological effect of this hormone on body fluid control, exerting an important role in osmolality urinary regulation. The hypothalamo-neurohypophysial system plays a fundamental role in the maintenance of hydromineral *Non-Reproductive Effects of Estradiol: Hydromineral Homeostasis Control DOI: http://dx.doi.org/10.5772/intechopen.95348*

homeostasis by secreting AVP and OT in response to osmotic and non-osmotic, and volemic stimuli (for review see [11]). Furthermore, in response to AT1 receptor activation, SFO efferent angiotensinergic projections increase the excitability of vasopressinergic and oxytocinergic neurons in the PVN and SON, leading to AVP and OT secretion [18]. ANGII also can directly increase AVP and OT secretion by acting on its AT1 receptor expressed in the PVN [19]. Concerning the ANGII signaling pathway in neurohypophysial secretion, Felgendreger et al. [20] showed that the ERK1/2 activation induced by endogenous ANGII is not involved in AVP and OT secretion in male rats. However, PKC involvement was not analyzed in this study.

#### **1.3 Interaction of body fluid balance with blood pressure control**

The balance of body fluid involves a close correlation with blood pressure control, and thus, disturbances in one of these imply adjustments in the other. The proper maintenance of cardiovascular functions, such as peripheral vascular tone, cardiac activity, and, consequently, blood pressure involves orchestrated activities of the sympathetic and parasympathetic nervous system. The sympathetic activity also exerts an important control renal function in the regulation of plasma volume and osmolality, which influence cardiovascular function [11]. Moreover, some of the key brain regions that are involved in the control of hydromineral homeostasis also promote adjustments in the neuroendocrine and autonomic mechanisms of blood pressure control. For example, the peripheral portion of the SFO sends projections to areas important for fluid balance (magnocellular neurosecretory neurons in the PVN and SON) while the core projects to areas involved in blood pressure control (parvocellular presympathetic neurons in the PVN) [5]. Thus, during disturbances of hydromineral homeostasis that lead to increased peripheral and central ANGII results in activation of neurosecretory and presympathetic neurons in the PVN, via afferent projections from the SFO, inducing an increased systemic AVP release and renal sympathetic outflow which act together to restore hydromineral balance [11]. AVP from neurosecretory neuronal populations also modulates sympathetic outflow and consequently blood pressure by increasing the activity of the presympathetic neurons within the PVN that project to the rostral ventrolateral medulla, a region responsible for the sympathetic system control on the cardiovascular function [21]. In addition, both circulating ANGII and AVP modulate blood pressure through its effects on peripheral vascular tone, inducing potent vasoconstriction and consequently increased total peripheral resistance [6, 11].

Taken together, SFO and hypothalamus, particularly PVN, play an important role in the generation of integrative homeostatic responses through orchestrated activities of neuroendocrine and autonomic networks [5, 11, 22]. An imbalanced interaction among these circuits results in maladaptive responses that can lead to an increased risk of developing cardiovascular disease, such as hypertension [23].

#### **1.4 Estradiol regulation of the hydromineral homeostasis**

It is well known that besides reproductive function and sexual behavior, ovarian gonadal hormones, mainly 17β-estradiol (E2), modulate other non-reproductive functions such as cardiovascular function, body fluid balance, feeding, sleep cycles, temperature regulation, mood, mental state, memory, and cognition [3, 24–30]. Nevertheless, in this chapter, we will discuss the main non-reproductive effects of estradiol on the control of hydromineral homeostasis, focusing on ingestive behavior and neurohypophyseal hormonal release.

Mounting evidence reports changes in the hydromineral balance associated with the different phases of the reproductive cycle, gestation period, and reproductive

senescence [3, 31, 32]. Receptor for estrogens (ER) is expressed in several tissues that play pivotal roles in hydromineral homeostasis, comprising the kidney, adrenal gland, blood vessels, and brain structures such as lamina terminalis (i.e., OVLT, MnPO, and SFO), and hypothalamus (PVN and SON) (for review see [33]). ER expression in the tissues that are involved in body fluid control supports the hypothesis that estrogens modulate hydromineral homeostasis control. Thus, the study of the influence of E2 on hydromineral homeostasis has been widely appreciated in recent decades, although the precise mechanism of its control is not always in agreement.

### **1.5 Estrogen receptor signaling**

Upon entering the cell, due to their lipophilic character, estrogens bind to their classical intranuclear receptors, which are classified as ER type alpha (ERα) and beta (ERβ), and mediate the regulation of genes and transcription factors, comprising their classic genomic signaling pathway. However, several studies have shown that estrogens can also trigger non-genomic events by binding plasmatic membrane-associated ER (mER), inducing rapid effects [34, 35]. In addition to other proteins, ER stimulation activates members of the MAPK family, such as ERK1/2, JNK, and p38 MAPK [30, 36, 37] as well increases PKC and PKA activities [38].

Importantly, most evidence supports that ERα and ERβ are trafficked to the membrane and also activated membrane estradiol cell signaling. Moreover, there are estrogen membrane-binding proteins that mediate estradiol non-genomic signaling, such as G protein-coupled estrogen receptor (GPER/GPR30), a putative receptor (ER-X), and splice variants of ERα and/or ERβ receptors (for review see [35]). However, the role of these mERs in estradiol signaling and effects remain to be better characterized.
