Neuroanatomical and functional identification of the purinergic signaling in hypothalamic nuclei involved in the control of body fluids and salt-induced hypertension

• Grant number: 19/19894-8
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2020
• End date: July 31, 2023
• 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
• Associated researchers: Paula Magalhães Gomes

Abstract

High salt intake is one of the causes of primary hypertension as it promotes an increase in plasma osmolarity by activating different brain regions that are susceptible to changes in neurotransmission by high sodium levels, leading to increased sympathetic nerve activity (SNA) and consequently increased in blood pressure (BP). Among the hypothalamic nuclei involved in neurogenic hypertension are the sensory circumventricular organs (CVOs): subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), due to the absence of blood-brain barrier, function as sodium sensors in the brain, sending excitatory projections to the paraventricular nucleus of the hypothalamus (PVN), which is an important integrating center of autonomic and neuroendocrine regulation. In past few years, our laboratory has published a series of studies demonstrating that adenosine triphosphate (ATP) increases the activity of PVN neurons and leads to increased ANS by activating purinergic receptors of the P2 subtype and also by a co-transmission with glutamatergic signalling. Recent studies we have demonstrated that an osmotic stimulus with hypertonic NaCl solution or mannitol (i.v.) elicited an intense activation of PVN (FOS protein expression) neurons, which also co-expressed P2X2 purinergic receptors. Taken together, these data suggest that the pressor and sympathetic excitation responses are related to the activation of purine-glutamatergic mechanisms in PVN pre-sympathetic neurons. However still is unknown about the origin of this purine an its action on the complex hypothalamic neuronal network. Thus, the aim of this project is to evaluate whether high salt-induced hypertension is of neurogenic origin, and dependent on purinergic signaling between the CVOs (SFO and OVLT) and the PVN, or is also due to changes in the content of body fluids, essentially volemia in this animal model of salt-dependent hypertension. For this we will use male Wistar rats, divided in two groups:1) circulating volume and hematocrit, by spectrophotometric evaluation of Evan's Blue dye; 2) ATP content in PVN by enzymatic assay; 3) real time detection of releasing of ATP, adenosine, glutamate and lactate in PVN, OVLT and SFO in response to a hyperosmotic challenge, using biosensors; 4) characterization of neuronal projections and phenotypes between OVLT/SFO-PVN, using neuronal tracing techniques, and immunohistochemistry for ATP (VNUT), and glutamate (VGLUT2) vesicles in SFO and OVLT; 5) identification of mRNA biomarkers for ATP and glutamate by RNAscope technique, and finally 6) to evaluate the purinergic signaling in PVN, by blocking P2 receptors, in response to osmotic stimuli in SFO and OVLT in control an the effects on the BP level and SNA. (AU)

Scientific publications

(6)

(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)

GOMES, PAULA MAGALHAES; BATISTA, JULIA SANTOS; SA, RENATO WILLIAN MARTINS; ANTUNES, VAGNER ROBERTO. Short exposure to high salt in drinking solution leads to a cardiovascular phenotype of hypertension without changes in the blood volume of rats. Experimental Physiology, v. N/A, p. 10-pg., 2023-01-30. (16/03359-8, 19/19894-8, 19/23588-0)

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)

PATON, JULIAN F. R.; MACHADO, BENEDITO H.; MORAES, DAVI J. A.; ZOCCAL, DANIEL B.; ABDALA, ANA P.; SMITH, JEFFREY C.; ANTUNES, VAGNER R.; MURPHY, DAVID; DUTSCHMANN, MATHIAS; DHINGRA, RISHI R.; et al. Advancing respiratory-cardiovascular physiology with the working heart-brainstem preparation over 25 years. JOURNAL OF PHYSIOLOGY-LONDON, v. 600, n. 9, p. 27-pg., 2022-04-07. (19/19894-8, 18/15957-2, 19/11863-6, 21/06886-7)

FREITAS, FLAVIO EDUARDO DIAS ARAUJO; BATISTA, MARCOS ADRIANO CARLOS; BRAGA, DAIANE CRISTINA DE ASSIS; DE OLIVEIRA, LISANDRA BRANDINO; ANTUNES, VAGNER ROBERTO; CARDOSO, LEONARDO MAXIMO. The gut-brain axis and sodium appetite: Can inflammation-related signaling influence the control of sodium intake. APPETITE, v. 175, p. 8-pg., 2022-08-01. (19/19894-8)

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)

LARANGEIRA, KAROLINE MARTINS DOS SANTOS; MORAES, DAVI JOSE DE ALMEIDA; DA SILVA, MELINA PIRES; ANTUNES, VAGNER ROBERTO. Exercise Training and Chemogenetic Activation of the Dorsal Motor Nucleus of the Vagus Rescue the Changes in the Hepatic Vein Glucose Concentration by Central Action of Insulin in SHR. FASEB JOURNAL, v. 36, p. 1-pg., 2022-01-01. (19/19894-8, 17/04532-8, 13/10484-5)