PMID- 27688999
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20161005
LR  - 20181113
IS  - 2212-8778 (Print)
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 5
IP  - 10
DP  - 2016 Oct
TI  - Mechanisms underlying prorenin actions on hypothalamic neurons implicated in 
      cardiometabolic control.
PG  - 858-868
LID - S2212-8778(16)30103-X [pii]
LID - 10.1016/j.molmet.2016.07.010 [doi]
AB  - 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.
FAU - Pitra, Soledad
AU  - Pitra S
AD  - Department of Physiology, Medical College of Georgia, Augusta University, United 
      States.
FAU - Feng, Yumei
AU  - Feng Y
AD  - Departments of Pharmacology, Physiology and Cell Biology, Center for 
      Cardiovascular Research, University of Nevada School of Medicine, United States.
FAU - Stern, Javier E
AU  - Stern JE
AD  - Department of Physiology, Medical College of Georgia, Augusta University, United 
      States. Electronic address: jstern@augusta.edu.
LA  - eng
GR  - R01 HL090948/HL/NHLBI NIH HHS/United States
GR  - R01 HL112225/HL/NHLBI NIH HHS/United States
GR  - R01 HL122770/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20160804
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
PMC - PMC5034613
OTO - NOTNLM
OT  - Angiotensin
OT  - PVN
OT  - Potassium
OT  - Prorenin receptor
OT  - SON
OT  - Sympathetic
EDAT- 2016/10/01 06:00
MHDA- 2016/10/01 06:01
PMCR- 2016/08/04
CRDT- 2016/10/01 06:00
PHST- 2016/07/13 00:00 [received]
PHST- 2016/07/26 00:00 [revised]
PHST- 2016/07/27 00:00 [accepted]
PHST- 2016/10/01 06:00 [entrez]
PHST- 2016/10/01 06:00 [pubmed]
PHST- 2016/10/01 06:01 [medline]
PHST- 2016/08/04 00:00 [pmc-release]
AID - S2212-8778(16)30103-X [pii]
AID - 10.1016/j.molmet.2016.07.010 [doi]
PST - epublish
SO  - Mol Metab. 2016 Aug 4;5(10):858-868. doi: 10.1016/j.molmet.2016.07.010. 
      eCollection 2016 Oct.