Salt-induced hypertension: role of purinergic signaling in the neuronal cells at the hypothalamus level, and its correlation with the autonomic nervous system and blood pressure control

• Grant number: 16/21991-3
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2017
• End date: October 31, 2019
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Vagner Roberto Antunes
• Grantee: Vagner Roberto Antunes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The main purpose of this project is to evaluate the mechanisms of purinergic neurotransmission between neuronal and glial cells of the paraventricular hypothalamic nucleus (PVN), whose changes in their neurochemistry directly involved in the control the autonomic nervous system (ANS), and the genesis of salt-induced hypertension. High salt intake leads to increase in the plasma osmolality, and consequently raise sympathetic nerve activity (SNA) by mechanisms that involve hypothalamic neuronal activation, particularly PVN, which contributes to neurogenic hypertension induced by high salt intake. Recently, our laboratory have shown that adenosine triphosphate (ATP) increases the activity of neurons in the PVN, and causes an increase of SNA via activation of purinergic receptors, P2 subtype, and a co-transmission with glutamatergic pathways. Thus, our hypothesis in this project is that hypertension and sympathoexcitation elicited by high salt intake depends on the purinergic signaling at the PVN level, and it involves a neuron/glia and ectonucleotidase interactions responsible for the availability of this purine at neuronal microenvironment of this nucleus. In turn, this phenomenon could be due a higher release of this purine by glial cells, which is consider to be a putative source of it, or at least a reduction of ectonucleotidases' activity. Male Wistar rats will be submitted to salt overload (NaCl 2%) to evaluate the expression of FOS protein and its co-location with P2X2 receptors in the PVN. In addition, it will be evaluated whether the P2 receptors participate in sympathoexcitatory responses to salt loading. Additionally, we purpose to evaluate if hyperosmotic stimulus is able to promote release of ATP within the PVN, by using biosensor that detects the release of this purine in real time. To evaluate the role of glial cells in ATP release, PVN cell cultures will be stimulated with hypertonic solution in the presence of fluoroacetate, a glial activity inhibitor. PCR technique will be performed to assess whether the salt loading modify the mRNA expression of enzymes ectonucleotidase (E-NTPDase1,2,3,8) in the PVN. The function of ectonucleotidades will be evaluated in vivo by using gene therapy techniques with lentivirus vector (LVV) encode transmembrane prostate acidic phosphatase (TMPAP) called of LVV-EF1a-TMPAP-EGFP to increase the expression of these enzymes at the PVN neuronal level. In this context, changes in cardiovascular parameters, blood pressure and heart rate will be evaluated in non-anesthetized freely moving animals via radiotelemetry technique. (AU)

Scientific publications

(11)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RIBEIRO, NATALIA; MARTINS SA, RENATO W.; ANTUNES, VAGNER R.. Depletion of C1 neurons attenuates the salt-induced hypertension in unanesthetized rats. Brain Research, v. 1748, DEC 1 2020. (16/21991-3, 13/06206-0)

ANTUNES, VAGNER; OLIVEIRA, ANGELO. Distinct Neuronal Excitability in the Paraventricular Nucleus of Hypothalamus after Baroreflex Challenge in Salt-Loaded Rats. FASEB JOURNAL, v. 35, p. 2-pg., 2021-05-01. (16/21991-3, 19/19894-8)

MALHEIROS-LIMA, MILENE R.; ANTUNES, VAGNER R.; TAKAKURA, ANA C.; MOREIRA, THIAGO S.. Hypertension and sympathetic nervous system overactivity rely on the vascular tone of pial vessels of the rostral ventrolateral medulla in spontaneously hypertensive rats. Experimental Physiology, v. 105, n. 1, p. 65-74, JAN 2020. (15/23376-1, 16/23281-3, 16/21991-3, 16/22069-0, 17/08696-5)

ROMEU, DEBORAH DE PAULA; RIBEIRO, LUCIENE MARIA; ANTUNES, VAGNER ROBERTO. Central action of CART induces neuronal activation in the paraventricular and dorsomedial hypothalamus of diet-induced obese and lean mice. Neuroscience Letters, v. 686, p. 175-180, NOV 1 2018. (15/07944-0, 16/21991-3, 13/06206-0)

FERREIRA-NETO, H. C.; ANTUNES, V. R.; STERN, J. E.. Purinergic P2 and glutamate NMDA receptor coupling contributes to osmotically driven excitability in hypothalamic magnocellular neurosecretory neurons. JOURNAL OF PHYSIOLOGY-LONDON, v. 599, n. 14, p. 3531-3547, JUL 2021. (10/17997-0, 12/12444-8, 10/05037-1, 16/21991-3)

SILVA, TALITA M.; CHAAR, LAIALI J.; SILVA, REINALDO C.; TAKAKURA, ANA C.; CAMARA, NIELS O.; ANTUNES, VAGNER R.; MOREIRA, THIAGO S.. Minocycline alters expression of inflammatory markers in autonomic brain areas and ventilatory responses induced by acute hypoxia. Experimental Physiology, v. 103, n. 6, p. 884-895, JUN 1 2018. (15/23376-1, 16/23281-3, 16/22069-0, 16/21991-3, 13/00401-5)

DOS SANTOS, KAROLINE MARTINS; MORAES, DAVI JOSE DE ALMEIDA; DA SILVA, MELINA PIRES; ANTUNES, VAGNER ROBERTO. Exercise training rescues the electrical activity of liver-projecting DMNV neurones in response to oxytocin in spontaneously hypertensive rats. Journal of Neuroendocrinology, v. 33, n. 5, MAY 2021. (16/21991-3, 19/11863-6)

FERREIRA-NETO, H. C.; RIBEIRO, I. M. R.; MOREIRA, T. S.; YAO, S. T.; ANTUNES, V. R.. PURINERGIC P2 RECEPTORS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS ARE INVOLVED IN HYPEROSMOTIC-INDUCED SYMPATHOEXCITATION. Neuroscience, v. 349, p. 253-263, MAY 4 2017. (10/05037-1, 13/06206-0, 16/21991-3, 10/17997-0)

MOREIRA, THIAGO S.; ANTUNES, VAGNER R.; FALQUETTO, BARBARA; MARINA, NEPHTALI. Long-term stimulation of cardiac vagal preganglionic neurons reduces blood pressure in the spontaneously hypertensive rat. Journal of Hypertension, v. 36, n. 12, p. 2444-2452, DEC 2018. (15/23376-1, 16/21991-3, 16/22069-0)

SA, RENATO W. MARTINS; THEPARAMBIL, SHEFEEQ M.; DOS SANTOS, KAROLINE MARTINS; CHRISTIE, ISABEL N.; MARINA, NEPHTALI; CARDOSO, BARBARA V.; HOSFORD, PATRICK S.; ANTUNES, VAGNER R.. Salt-loading promotes extracellular ATP release mediated by glial cells in the hypothalamic paraventricular nucleus of rats. Molecular and Cellular Neuroscience, v. 124, p. 9-pg., 2023-01-18. (19/19894-8, 16/21991-3, 16/03359-8, 18/19907-0)

SA, RENATO WILLIAN MARTINS; RIBEIRO, NATALIA; RIBEIRO, LUCIENE MARIA; MENDONCA, JOHNNY MENDES; SANTOS, KAROL MARTINS; ANTUNES, VAGNER ROBERTO. Ectonucleotidases in the Hypothalamus of Salt-Induced Hypertensive Rats: Transcriptional Profile and functional implications. FASEB JOURNAL, v. 32, n. 1, p. 2-pg., 2018-04-01. (16/21991-3, 16/03359-8)