Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control

Soledad Pitra, Yumei Feng, Javier E. Stern

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background Hypertension and obesity are highly interrelated diseases, being critical components of the metabolic syndrome. Despite the growing prevalence of this syndrome in the world population, efficient therapies are still missing. Thus, identification of novel targets and therapies are warranted. An enhanced activity of the hypothalamic renin-angiotensin system (RAS), including the recently discovered prorenin (PR) and its receptor (PRR), has been implicated as a common mechanism underlying aberrant sympatho-humoral activation that contributes to both metabolic and cardiovascular dysregulation in the metabolic syndrome. Still, the identification of precise neuronal targets, cellular mechanisms and signaling pathways underlying PR/PRR actions in cardiovascular- and metabolic related hypothalamic nuclei remain unknown. Methods and results Using a multidisciplinary approach including patch-clamp electrophysiology, live calcium imaging and immunohistochemistry, we aimed to elucidate cellular mechanisms underlying PR/PRR actions within the hypothalamic supraoptic (SON) and paraventricular nucleus (PVN), key brain areas previously involved in cardiometabolic regulation. We show for the first time that PRR is expressed in magnocellular neurosecretory cells (MNCs), and to a lesser extent, in presympathetic PVN neurons (PVNPS). Moreover, we show that while PRR activation efficiently stimulates the firing activity of both MNCs and PVNPS neurons, these effects involved AngII-independent and AngII-dependent mechanisms, respectively. In both cases however, PR excitatory effects involved an increase in intracellular Ca2+ levels and a Ca2+-dependent inhibition of a voltage-gated K+ current. Conclusions We identified novel neuronal targets and cellular mechanisms underlying PR/PRR actions in critical hypothalamic neurons involved in cardiometabolic regulation. This fundamental mechanistic information regarding central PR/PRR actions is essential for the development of novel RAS-based therapeutic targets for the treatment of cardiometabolic disorders in obesity and hypertension.

Original languageEnglish (US)
Pages (from-to)858-868
Number of pages11
JournalMolecular Metabolism
Volume5
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Renin
Neurons
Paraventricular Hypothalamic Nucleus
Renin-Angiotensin System
Obesity
Hypertension
Supraoptic Nucleus
Electrophysiology
Therapeutics
Immunohistochemistry
Calcium
Brain
Population

Keywords

  • Angiotensin
  • Potassium
  • Prorenin receptor
  • PVN
  • SON
  • Sympathetic

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. / Pitra, Soledad; Feng, Yumei; Stern, Javier E.

In: Molecular Metabolism, Vol. 5, No. 10, 01.10.2016, p. 858-868.

Research output: Contribution to journalArticle

Pitra, Soledad ; Feng, Yumei ; Stern, Javier E. / Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. In: Molecular Metabolism. 2016 ; Vol. 5, No. 10. pp. 858-868.
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abstract = "Background Hypertension and obesity are highly interrelated diseases, being critical components of the metabolic syndrome. Despite the growing prevalence of this syndrome in the world population, efficient therapies are still missing. Thus, identification of novel targets and therapies are warranted. An enhanced activity of the hypothalamic renin-angiotensin system (RAS), including the recently discovered prorenin (PR) and its receptor (PRR), has been implicated as a common mechanism underlying aberrant sympatho-humoral activation that contributes to both metabolic and cardiovascular dysregulation in the metabolic syndrome. Still, the identification of precise neuronal targets, cellular mechanisms and signaling pathways underlying PR/PRR actions in cardiovascular- and metabolic related hypothalamic nuclei remain unknown. Methods and results Using a multidisciplinary approach including patch-clamp electrophysiology, live calcium imaging and immunohistochemistry, we aimed to elucidate cellular mechanisms underlying PR/PRR actions within the hypothalamic supraoptic (SON) and paraventricular nucleus (PVN), key brain areas previously involved in cardiometabolic regulation. We show for the first time that PRR is expressed in magnocellular neurosecretory cells (MNCs), and to a lesser extent, in presympathetic PVN neurons (PVNPS). Moreover, we show that while PRR activation efficiently stimulates the firing activity of both MNCs and PVNPS neurons, these effects involved AngII-independent and AngII-dependent mechanisms, respectively. In both cases however, PR excitatory effects involved an increase in intracellular Ca2+ levels and a Ca2+-dependent inhibition of a voltage-gated K+ current. Conclusions We identified novel neuronal targets and cellular mechanisms underlying PR/PRR actions in critical hypothalamic neurons involved in cardiometabolic regulation. This fundamental mechanistic information regarding central PR/PRR actions is essential for the development of novel RAS-based therapeutic targets for the treatment of cardiometabolic disorders in obesity and hypertension.",
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