Na x-positive glial cells in the organum vasculosum laminae terminalis produce epoxyeicosatrienoic acids to induce water intake in response to increases in [Na +] in body fluids

Neurosci Res. 2020 May;154:45-51. doi: 10.1016/j.neures.2019.05.006. Epub 2019 May 28.

Abstract

Nax is a [Na+] sensor expressed in specific glial cells in the sensory circumventricular organs (sCVOs) in the brain. We recently demonstrated that Nax signals are involved in the control of not only salt intake but also water intake behavior. Our pharmacological experiments suggested that Nax signals led to activation of neurons bearing TRPV4 by using epoxyeicosatrienoic acids (EETs) as gliotransmitters to stimulate water intake. In the present study, we performed selective lesions of individual sCVOs in wild-type (WT) mice and the site-directed rescue of Nax expression in Nax-gene knockout (Nax-KO) mice. These experiments revealed that the Nax channel in the organum vasculosum laminae terminalis (OVLT) functions as a [Na+] sensor for the control of water intake behavior. Direct measurements of 5,6-EET and 8,9-EET in the OVLT demonstrated that EET levels were indeed increased two-fold by water deprivation for two days in WT, but not Nax-KO mice, indicating that EETs were Nax-dependently produced in the OVLT in response to increases in [Na+] in body fluids. More importantly, intracerebroventricular injection of 5,6-EET at the same level was effective to induce water intake. Double staining revealed that Nax-positive cells also expressed Cyp2c44, a cytochrome P450 epoxygenase, to generate EETs. Collectively, these results indicate that Nax-positive glial cells produce EETs to activate TRPV4-positive neurons which may stimulate water intake, in response to increases in [Na+] of body fluids.

Keywords: Cyp2c44; Epoxyeicosatrienoic acids; Na(x)organum vasculosum laminae terminalis; TRPV4; Water intake.

MeSH terms

  • Animals
  • Body Fluids / physiology*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Cytochrome P450 Family 2 / metabolism
  • Drinking / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuroglia / metabolism*
  • Neurons / metabolism
  • Organum Vasculosum / metabolism*
  • Sodium / metabolism*
  • TRPV Cation Channels / metabolism
  • Voltage-Gated Sodium Channels / metabolism*

Substances

  • Scn7a protein, mouse
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Voltage-Gated Sodium Channels
  • Cytochrome P-450 Enzyme System
  • Sodium
  • Cyp2c23 protein, mouse
  • Cytochrome P450 Family 2
  • arachidonate epoxygenase