Angiotensin type-2 receptors influence the activity of vasopressin neurons in the paraventricular nucleus of the hypothalamus in male mice

Annette D. De Kloet, Soledad Pitra, Lei Wang, Helmut Hiller, David J. Pioquinto, Justin A. Smith, Colin Sumners, Javier Eduardo Stern, Eric G. Krause

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Abstract

It is known that angiotensin-II acts at its type-1 receptor to stimulate vasopressin (AVP) secretion, which may contribute to angiotensin-II-induced hypertension. Less well known is the impact of angiotensin type-2 receptor (AT2R) activation on these processes. Studies conducted in a transgenic AT2R enhanced green fluorescent protein reporter mouse revealed that although AT2R are not themselves localized to AVP neurons within the paraventricular nucleus of the hypothalamus (PVN), they are localized to neurons that extend processes into the PVN. In the present set of studies, we set out to characterize the origin, phenotype, and function of nerve terminals within the PVN that arise from AT2R-enhanced green fluorescent protein-positive neurons and synapse onto AVP neurons. Initial experiments combined genetic and neuroanatomical techniques to determine that γ-aminobutyric acid (GABA)ergic neurons derived from the peri-PVN area containing AT2R make appositions onto AVP neurons within the PVN, thereby positioning AT2R to negatively regulate neuroendocrine secretion. Subsequent patch-clamp electrophysiological experiments revealed that selective activation of AT2R in the peri-PVN area using compound 21 facilitates inhibitory (ie, GABAergic) neurotransmission and leads to reduced activity of AVP neurons within the PVN. Final experiments determined the functional impact of AT2R activation by testing the effects of compound21 on plasma AVP levels. Collectively, these experiments revealed that AT2R expressing neurons make GABAergic synapses onto AVP neurons that inhibit AVP neuronal activity and suppress baseline systemic AVP levels. These findings have direct implications in the targeting of AT2R for disorders of AVP secretion and also for the alleviation of high blood pressure. (Endocrinology 157: 3167-3180, 2016)

Original languageEnglish (US)
Pages (from-to)3167-3180
Number of pages14
JournalEndocrinology
Volume157
Issue number8
DOIs
StatePublished - Aug 2016

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Angiotensin Type 2 Receptor
Paraventricular Hypothalamic Nucleus
Vasopressins
Hypothalamus
Neurons
GABAergic Neurons
Angiotensin II
Synapses
Hypertension
Aminobutyrates
Genetic Techniques
Endocrinology
Synaptic Transmission

ASJC Scopus subject areas

  • Endocrinology

Cite this

De Kloet, A. D., Pitra, S., Wang, L., Hiller, H., Pioquinto, D. J., Smith, J. A., ... Krause, E. G. (2016). Angiotensin type-2 receptors influence the activity of vasopressin neurons in the paraventricular nucleus of the hypothalamus in male mice. Endocrinology, 157(8), 3167-3180. https://doi.org/10.1210/en.2016-1131

Angiotensin type-2 receptors influence the activity of vasopressin neurons in the paraventricular nucleus of the hypothalamus in male mice. / De Kloet, Annette D.; Pitra, Soledad; Wang, Lei; Hiller, Helmut; Pioquinto, David J.; Smith, Justin A.; Sumners, Colin; Stern, Javier Eduardo; Krause, Eric G.

In: Endocrinology, Vol. 157, No. 8, 08.2016, p. 3167-3180.

Research output: Contribution to journalArticle

De Kloet, AD, Pitra, S, Wang, L, Hiller, H, Pioquinto, DJ, Smith, JA, Sumners, C, Stern, JE & Krause, EG 2016, 'Angiotensin type-2 receptors influence the activity of vasopressin neurons in the paraventricular nucleus of the hypothalamus in male mice', Endocrinology, vol. 157, no. 8, pp. 3167-3180. https://doi.org/10.1210/en.2016-1131
De Kloet, Annette D. ; Pitra, Soledad ; Wang, Lei ; Hiller, Helmut ; Pioquinto, David J. ; Smith, Justin A. ; Sumners, Colin ; Stern, Javier Eduardo ; Krause, Eric G. / Angiotensin type-2 receptors influence the activity of vasopressin neurons in the paraventricular nucleus of the hypothalamus in male mice. In: Endocrinology. 2016 ; Vol. 157, No. 8. pp. 3167-3180.
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