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Pitra S, Feng Y, Stern JE. Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. Mol Metab. 2016;5(10):858-868doi: 10.1016/j.molmet.2016.07.010.
Pitra, S., Feng, Y., & Stern, J. E. (2016). Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. Molecular metabolism, 5(10), 858-868. https://doi.org/10.1016/j.molmet.2016.07.010
Pitra, Soledad, et al. "Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control." Molecular metabolism vol. 5,10 (2016): 858-868. doi: https://doi.org/10.1016/j.molmet.2016.07.010
Pitra S, Feng Y, Stern JE. Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. Mol Metab. 2016 Aug 04;5(10):858-868. doi: 10.1016/j.molmet.2016.07.010. eCollection 2016 Oct. PMID: 27688999; PMCID: PMC5034613.
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Mol Metab. 2016 Aug 04;5(10):858-868. doi: 10.1016/j.molmet.2016.07.010. eCollection 2016 Oct.

Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control.

Molecular metabolism

Soledad Pitra, Yumei Feng, Javier E Stern

Affiliations

  1. Department of Physiology, Medical College of Georgia, Augusta University, United States.
  2. Departments of Pharmacology, Physiology and Cell Biology, Center for Cardiovascular Research, University of Nevada School of Medicine, United States.
  3. Department of Physiology, Medical College of Georgia, Augusta University, United States. Electronic address: [email protected].

PMID: 27688999 PMCID: PMC5034613 DOI: 10.1016/j.molmet.2016.07.010

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 Ca(2+) levels and a Ca(2+)-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.

Keywords: Angiotensin; PVN; Potassium; Prorenin receptor; SON; Sympathetic

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