title: Astrocytes Contribute to Angiotensin II Stimulation of Hypothalamic Neuronal Activity and Sympathetic Outflow.
abstract: Angiotensin II (AngII) is a key neuropeptide that acting within the brain hypothalamic paraventricular nucleus regulates neurohumoral outflow to the circulation. Moreover, an exacerbated AngII action within the paraventricular nucleus contributes to neurohumoral activation in hypertension. Although AngII effects involve changes in paraventricular nucleus neuronal activity, the precise underlying mechanisms, cellular targets, and distribution of AngII receptors within the paraventricular nucleus remain largely unknown. Thus, whether AngII effects involve direct actions on paraventricular neurons, or whether it acts via intermediary cells, such as astrocytes, is still controversial. To address this important gap in our knowledge, we used a multidisciplinary approach combining patch-clamp electrophysiology in presympathetic paraventricular neurons and astrocytes, along with in vivo sympathetic nerve recordings and astrocyte-targeted gene manipulations. We present evidence for a novel mechanism underlying central AngII actions, which involves astrocytes as major intermediary cellular targets. We found that AngII type 1 receptor mRNA is expressed in paraventricular astrocytes. Moreover, we report that AngII inhibited glutamate transporter function, increasing in turn extracellular glutamate levels. This resulted in the activation of neuronal extrasynaptic NMDA (N-methyl-d-aspartate) receptors, increased presympathetic neuronal activity, enhanced sympathoexcitatory outflow, and increased blood pressure. Together, our studies support astrocytes as critical intermediary cell types mediating brain AngII regulation of the circulation and indicate that AngII-mediated neuronal and sympathoexcitatory effects are dependent on a unique neuroglial signaling modality involving nonsynaptic glutamate transmission.
authors.affiliation: From the Department of Physiology, Augusta University, GA (J.E.S., S.S., V.C.B.); and Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (H.Z., N.S., K.P.P.). jstern@augusta.edu.
authors.forename: Javier E
authors.initials: JE
authors.lastname: Stern
authors.affiliation: From the Department of Physiology, Augusta University, GA (J.E.S., S.S., V.C.B.); and Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (H.Z., N.S., K.P.P.).
authors.forename: Sookjin
authors.initials: S
authors.lastname: Son
authors.affiliation: From the Department of Physiology, Augusta University, GA (J.E.S., S.S., V.C.B.); and Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (H.Z., N.S., K.P.P.).
authors.forename: Vinicia C
authors.initials: VC
authors.lastname: Biancardi
authors.affiliation: From the Department of Physiology, Augusta University, GA (J.E.S., S.S., V.C.B.); and Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (H.Z., N.S., K.P.P.).
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: From the Department of Physiology, Augusta University, GA (J.E.S., S.S., V.C.B.); and Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (H.Z., N.S., K.P.P.).
authors.forename: Neeru
authors.initials: N
authors.lastname: Sharma
authors.affiliation: From the Department of Physiology, Augusta University, GA (J.E.S., S.S., V.C.B.); and Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (H.Z., N.S., K.P.P.).
authors.forename: Kaushik P
authors.initials: KP
authors.lastname: Patel
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D004594:Electrophysiology; D018698:Glutamic Acid / Q000378:metabolism*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
chemical_list: D000804:Angiotensin II; D018698:Glutamic Acid
keywords: angiotensin; astrocyte; blood pressure; heart failure; hypothalamus