Na_x signaling evoked by an increase in [Na⁺] in CSF induces water intake via EET-mediated TRPV4 activation

Abstract

-Water-intake behavior is under the control of brain systems that sense body fluid conditions at sensory circumventricular organs (sCVOs); however, the underlying mechanisms have not yet been elucidated in detail. Na x is a sodium (Na ϩ ) level sensor in the brain, and the transient receptor potential vanilloid (TRPV) channels TRPV1 and TRPV4 have been proposed to function as osmosensors. We herein investigated voluntary water intake immediately induced after an intracerebroventricular administration of a hypertonic NaCl solution in TRPV1-, TRPV4-, Na x-, and their doublegene knockout (KO) mice. The induction of water intake by TRPV1-KO mice was normal, whereas intake by TRPV4-KO and Na x-KO mice was significantly less than that by WT mice. Water intake by Nax/TRPV4-double KO mice was similar to that by the respective single KO mice. When TRPV4 activity was blocked with a specific antagonist HC-067047, water intake by WT mice was significantly reduced, whereas intake by TRPV4-KO and Na x-KO mice was not. Similar results were obtained with the administration of miconazole, which inhibits the biosynthesis of epoxyeicosatrienoic acids (EETs), endogenous agonists for TRPV4, from arachidonic acid (AA). Intracerebroventricular injection of hypertonic NaCl with AA or 5,6-EET restored water intake by Nax-KO mice to the wild-type level but not that by TRPV4-KO mice. These results suggest that the Na ϩ signal generated in Nax-positive glial cells leads to the activation of TRPV4-positive neurons in sCVOs to stimulate water intake by using EETs as gliotransmitters. Intracerebroventricular injection of equiosmolar hypertonic sorbitol solution induced small but significant water intake equally in all the genotypes, suggesting the presence of an unknown osmosensor in the brain. TRPV1; TRPV4; Nax; water intake; epoxyeicosatrienoic acid MAMMALS possess a set of homeostatic mechanisms that function together to maintain body fluid osmolality at approximately 300 mosmol/kg H 2 O by controlling the intake and excretion of water and salt (4, 5). This homeostatic osmoregulation is vital because changes in cell volume due to severe hypertonicity or hypotonicity cause irreversible damage to organs and lethal neurological trauma (6,8,46). Animals exhibit prominent and effective responses to dehydration, including behavioral responses, such as water intake and salt aversion, and vasopressin (VP)-induced reductions in urine volume (39). Central and peripheral sensing systems for body fluid conditions have been shown to contribute to body fluid homeostasis (10).The Na ϩ ion is the main determinant of osmolality in vivo. When animals are dehydrated, osmolality in body fluids increases along with elevations in the concentration of Na McKinley et al. (33,35) previously reported that the injection of a hypertonic NaCl solution into the third ventricle of conscious sheep induced stronger antidiuretic and drinking responses than that of an equiosmolar hypertonic sucrose solution. Therefore, they speculated that a Na ϩ sensor other than osmosenso...

Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ

“…II.7E). In addition, prof. Noda's laboratory recently found that Na x signals were also involved in the immediate induction of water intake evoked by an intracerebroventricular administration of a hypertonic NaCl solution (Sakuta et al, 2016); Here, Na x in the OVLT appears to mediate this function (unpublished observation in prof. Noda's laboratory). Moreover, activation of OVLT neurons expressing vasopressin receptor 1a is reported to be involved in water intake to prevent anticipatory thirst during sleep period (Gizowski et al, 2016).…”

“…receptor-positive neurons may be also involved in water-intake control, and that some other water neurons are also present in the SFO and OVLT, which are activated by signals of Na + , osmolality, or other dipsogenic hormones (Fitzsmons, 1998;Li et al, 2003;Sakuta et al, 2016). Under the Na-depleted condition (right), salt neurons which innervate the vBNST are activated by Ang II and enhance salt appetite.…”

[Na+] Increases in Body Fluids Sensed by Central Nax Induce Sympathetically Mediated Blood Pressure Elevations via H+-Dependent Activation of ASIC1a

“…As expected, lactate enhanced the H + -induced activation of OVLT(/PVN) neurons ( Figure 4F). Notably, the Na x signal may lead to the production of epoxyeicosatrienoic acids (EETs) in the OVLT through the activation of the AA cascade (Sakuta et al, 2016). Since treatments with hyperosmotic mannitol solution did not activate pH-sensitive OVLT(/PVN) neurons ( Figure 4G), osmotic changes (induced by hypertonic Na solution) did not appear to activate ASIC1a-positive OVLT(/PVN) neurons.…”

“…We also showed that the SFO is the principal site for sensing [Na + ] in body fluids by Na x to control salt appetite (Hiyama et al, 2004;Matsuda et al, 2017). Our recent findings suggested that the Na x signal in sCVOs is also involved in water-intake control (Sakuta et al, 2016). However, possible roles for Na x in BP control have not yet been elucidated.…”

Na+ homeostasis by epithelial Na+ channel (ENaC) and Nax channel (Nax): cooperation of ENaC and Nax

“…Thus, the low GFR due to a decrease in the circulating blood caused by low body Na + content increases renin release, leading to elevation of body Na + content due to an increase in Na + reabsorption via aldosterone-induced increases of ENaC production and surface expression in the collecting duct. Further, recently Na x has been reported to be a Na + concentration-sensitive Na + channel acting as a Na + sensor (46)(47)(48)(49)(50)(51)(52)(53)60,61). Na x was found in the brain as an atypical Na + channel, poorly homologous to the voltage-gated Na + channels (62).…”