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


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.
Department of Physiology, Medical College of Georgia, Augusta University, United States.
Soledad
S
Pitra
Departments of Pharmacology, Physiology and Cell Biology, Center for Cardiovascular Research, University of Nevada School of Medicine, United States.
Yumei
Y
Feng
Department of Physiology, Medical College of Georgia, Augusta University, United States. Electronic address: jstern@augusta.edu.
Javier E
JE
Stern
Angiotensin; PVN; Potassium; Prorenin receptor; SON; Sympathetic
Endocrinology. 2013 Feb;154(2):589-96
23270805
Hypertension. 2013 Mar;61(3):622-7
23319541
Glia. 2014 Jan;62(1):17-25
24166765
J Comp Neurol. 2010 Mar 1;518(5):567-85
20034060
Endocrinology. 2009 Sep;150(9):4114-23
19497971
Physiol Behav. 2014 Sep;136:31-8
24508821
Kidney Int. 2006 Jan;69(1):105-13
16374430
J Neurosci. 2013 Mar 13;33(11):4825-33
23486953
J Physiol. 1998 Dec 1;513 ( Pt 2):493-506
9806998
Cell Calcium. 2012 Mar-Apr;51(3-4):293-9
22386684
J Hypertens. 2004 Oct;22(10):1977-82
15361770
PLoS One. 2014 Oct 10;9(10):e92937
25302502
PLoS One. 2013;8(3):e59625
23527232
Hypertension. 2010 Aug;56(2):297-303
20547972
Hypertension. 2012 Jun;59(6):1188-94
22526255
Hypertension. 2015 Feb;65(2):352-61
25421983
Am J Physiol. 1985 Mar;248(3 Pt 2):R271-81
3883813
Circ Res. 2010 Oct 1;107(7):934-8
20689062
Hypertension. 2016 Jul;68(1):213-9
27185751
Am J Physiol Heart Circ Physiol. 2015 Sep;309(5):H880-7
26116710
J Physiol. 2001 Nov 15;537(Pt 1):161-77
11711570
Neuroscience. 1980;5(11):1931-58
7432630
Cell Metab. 2010 Nov 3;12(5):431-42
21035755
J Physiol. 2009 Sep 1;587(Pt 17):4235-47
19581379
Hypertension. 2010 Apr;55(4):862-8
20194306
Nat Rev Neurosci. 2006 May;7(5):335-46
16760914
Hypertension. 2014 Feb;63(2):316-23
24246383
J Neurophysiol. 2010 Jan;103(1):4-15
19889858
Prev Med. 1987 Mar;16(2):235-51
3588564
Neuron. 1996 Jan;16(1):151-62
8562079
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13415-20
10557335
PLoS One. 2013;8(3):e58339
23516464
Obesity (Silver Spring). 2014 Oct;22(10):2201-9
25044950
Hypertens Res. 2007 Nov;30(11):1139-46
18250563
Science. 1983 Aug 26;221(4613):869-71
6879184
Hypertension. 2008 Mar;51(3):682-8
18212269
J Physiol. 2011 Feb 1;589(Pt 3):667-83
21149460
Hypertension. 2012 Nov;60(5):1280-6
23033372
J Neurophysiol. 1985 Dec;54(6):1375-82
4087038
J Comp Neurol. 2013 Jul 1;521(10):2208-34
23605441
Am J Physiol Regul Integr Comp Physiol. 2004 Oct;287(4):R943-9
15191907
Eur J Neurosci. 2009 Jun;29(12):2335-46
19490083
Physiol Behav. 2010 Jul 14;100(5):525-34
20381510
Brain Res. 2003 Jan 3;959(1):20-8
12480154
Hypertension. 2016 Jan;67(1):163-70
26573717
J Hypertens. 1998 May;16(5):571-5
9797167
J Physiol. 2005 Jul 15;566(Pt 2):505-18
15878948
Endocrinology. 2005 Jan;146(1):406-13
15375027
Am J Physiol Endocrinol Metab. 2004 Jun;286(6):E891-5
14749209
J Physiol. 1982 Sep;330:537-72
6294290
J Clin Endocrinol Metab. 2008 Nov;93(11 Suppl 1):S37-50
18987269
J Neurophysiol. 2011 Sep;106(3):1545-57
21697450
Diabetes. 2013 Aug;62(8):2629-34
23881189
J Clin Invest. 2002 Jun;109(11):1417-27
12045255
Mol Endocrinol. 2008 Jul;22(7):1723-34
18451093
Am J Physiol Regul Integr Comp Physiol. 2004 Aug;287(2):R422-8
15117728
Hypertension. 2013 Mar;61(3):628-34
23339171
Cardiovasc Res. 2014 Jul 1;103(1):17-27
24667851
Endocrinology. 2014 Jul;155(7):2436-44
24773343
Am J Physiol Heart Circ Physiol. 2012 Jul 15;303(2):H197-206
22610169
Hypertension. 2013 Jan;61(1):253-8
23150519
Neuron. 2013 Jun 19;78(6):1036-49
23791197
Trends Pharmacol Sci. 2008 Jul;29(7):367-74
18579222
Int J Biochem Cell Biol. 2003 Jun;35(6):901-18
12676175
Hypertension. 2016 May;67(5):970-6
27021010
J Physiol. 1997 Nov 15;505 ( Pt 1):95-106
9409474
Am J Physiol Regul Integr Comp Physiol. 2013 Aug 15;305(4):R414-22
23785079