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Integrative studies of the body fluid homeostasis: physiological and molecular aspects of the neuroendocrine control and clinical and experimental evaluation


The control of hydromineral balance is complex and has stimulated the investigation of afferent and efferent inputs involved in this physiological paradigm. In mammals, the regulation of volume and plasma osmolality involves the participation of osmoreceptores/sodium receptors, as well as volume or baroreceptors that receive information from the alterations of the hydromineral balance, which are integrated in specific areas of central nervous system (CNS). These areas include the AV3V region (OVLT and MnPO), subfornical organ (SFO), paraventricular (PVN) and supraoptic nucleus (SON), locus ceruleus, dorsal nucleus of raphe and lateral parabrachial nucleus. These structures are involved in the induction of thirst and sodium appetite, activation of the sympathetic system and of renin-angiotensin-aldosterone system (RAAS) , secretion of vasopressin (AVP) and oxytocin (OT), and atrial natriuretic peptide (ANP) release from the heart. ANP is mainly located in the heart, however, the presence of ANP and ANP receptors have also been described in areas of the CNS involved in the control of circulating volume and blood pressure, such as hypothalamus and the brain stem. Blood volume expansion has been shown to induce afferent inputs through baroreceptors, leading to ANP release from the brain. There is an interaction between the ANPergic system and the neurohypophysial hormones, mainly OT, as suggested by the reduction of plasma ANP following blood volume expansion in animals with lesion of median eminence or neurohypophysectomy. Results from our laboratory have indicated that there is an integrative control of water and electrolyte balance involving the participation of OT, AVP and ANP. Nitric oxide (NO) has been considered as a local modulator of the activity of the magnocellular neurons. Other factors such as the cholinergic, adrenergic, and serotoninergic systems are also involved in the regulation of hydromineral balance. In the Project 1 we aimed to evaluate the mechanisms involved in the OT, AVP, and ANP release, as well as the participation of nitric oxide and other factors in the modulation of these mechanisms. Thus, the Project 1 "The neuroendocrine control of hydroelectrolytic balance" will be subdivided in: Sub-project 1.1: "Neuroendocrine control of hydroelectrolytic balance: participation of the serotonin and oxytocin " Sub-design 1.2: Correlation of expression of c-fos and oxytocin in the CNS structures with plasma concentration of ANP, AVP and OT, after osmotic, angiotensinergic and cholinergic stimulation. Sub-design 1.3: The participation of nitric oxide in the control of vasopressin and oxytocin secretion. Sub-design 1.4: Participation and characterization of angiotensinergic and serotoninergic pathways in the control of sodium appetite in rats. Sub-design 1.5: Participation of serotonergic pathways and lateral parabrachial nucleus in the regulation of neuroendocrine responses in the control of the blood volume and plasma osmolality. Sub-design 1.6: Effect of osmolality variation on the atrial natriuretic peptide (ANP) secretion from the basal hypothalamus in an in vitro study: nitrergic modulation. Sub-design 1.7: Regulation of AN P release in primary culture of atrial cardiomyocyte. Under stress conditions, there is an activation of several systems, including the autonomic, neuroendocrine system (hypothalamic-pituitary-adrenal axis and cardiovascular system. Nitric oxide has been implicated in the variations of plasma concentrations of several hormones (prolactin, AVP, and OT) in response to stress induced by Iypopolysacharide (LPS). In the Project 2 "Regulation of oxytocin, vasopressin and prolactin release during the experimental septic shock Ii we will evaluate the participation of NO and CO as mediators of OT, AVP and PRL secretion after stress induced by LPS. AVP is present not only in the magnocellular neurons but also in the parvocellular neurons of the PVN, where it is co-localized with corticotrophin releasing hormone (CRH). The synergic action of parvocellular AVP in the potentiation of CRH effect on the control of pituitary-adrenal function is well established. On the other hand, the role of magnocellular AVP in the regulation of ACTH secretion is still controversial. The experimental procedures that evaluate the molecular mechanisms involved in the HPA axis regulation, under adrenocortical deficiency induced by adrenalectomy, stress and the interaction with feeding are depicted in the Project 3 "Regulation of hypothalamus-pituitary-adrenal axis" that includes the following sub-projects: Sub-project 3.1: Expression of corticotrophin releasing hormone receptor (CRH-R1, CRH-R2 alfa, CRH-R2 beta) and vasopressin receptor (V1b) after adrenalectomy in basal conditions and after stress. Sub-project 3.2: Interaction of hypothalamus-pituitary-adrenal axis and the central melanocortin system. Congenital and acquired vasopressin deficiency (central diabetes insipidus) allows the investigation of interaction of vasopressin and HPA axis. In the present study we aimed to characterize the molecular basis of central diabetes insipidus in a Brazilian family with this rare disease. We will also use an experimental model of diabetes insipidus in rats to evaluate the HPA axis in the absence of magnocellular AVP. In the Project 4 "Central diabetes insipidus" we will study the AVP-NPII gene in patients with familial central diabetes insipidus. In the experimental model we will also evaluate the AVP and CRH expression in the hypothalamus in response to osmotic stimulus. Renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the extracellular volume regulation. The hydroelectrolytic homeostasis is maintained through an interplay of mechanisms that reduce sodium and water excretion, such as RAAS, vasopressin, and autonomic nervous system, with those mechanisms that increase urinary excretion such as ANP, prostaglandin and NO. In the Project 5 "Congenital adrenal hyperplasia and the hydroelectrolytic homeostasis" we aimed to evaluate these systems in a clinical model of RAAS alterations. We will conduct molecular study of 21-hydroxylase and 11 beta hydroxylase deficiencies. We will also study the interaction of ANP and RAAS in patients with 21-hydroxylase deficiency under basal conditions and after head down tilting. The Project 5 is subdivide in: Sub-project 5.1: Congenital adrenal hyperplasia due to 21-hydroxylase Deficiency Sub-project 5.2: Molecular study of 21-hydroxylase deficiency: genotype and phenotype correlation Sub-project 5.3: Molecular analysis of CYP11B1 gene and functional study in heterozygotes for 11 beta hydroxylase deficiency. To develop this project we will use techniques available in the laboratory including stereotaxic surgery, intracerebroventricular injection system, minipumps, neurohypophysectomy, adrenalectomy functional evaluation of HPA axis and hydroelectrolyte homeostasis. We will also use molecular biology techniques such as in situ hybridization, ribonuclease protection assay, Western blot, immunocitochemistry, PCR, and automated sequencing. (AU)

Scientific publications (7)
(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)
SOUZA, MANOEL CARLOS L. A.; MARTINS, CLARISSA S.; SILVA-JUNIOR, IVAN M.; CHRIGUER, ROSANGELA S.; BUENO, ANA C.; ANTONINI, SONIR R.; SILVA, JR., WILSON ARAUJO; ZAGO, MARCO A.; MOREIRA, AYRTON C.; DE CASTRO, MARGARET. NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 58, n. 1, p. 53-61, FEB 2014. Web of Science Citations: 10.
L.O. MARGATHO; L.L.K. ELIAS; J. ANTUNES-RODRIGUES. GABA in the central amygdaloid nucleus modulates the electrolyte excretion and hormonal responses to blood volume expansion in rats. Brazilian Journal of Medical and Biological Research, v. 42, n. 1, p. 114-121, Jan. 2009.
MARGATHO, LISANDRA OLIVEIRA; GODINO, ANDREA; TENORIO OLIVEIRA, FABIOLA RAQUEL; VIVAS, LAURA; ANTUNES-RODRIGUES, JOSE. Lateral Parabrachial Afferent Areas and Serotonin Mechanisms Activated by Volume Expansion. Journal of Neuroscience Research, v. 86, n. 16, p. 3613-3621, DEC 2008. Web of Science Citations: 13.
BADAUÊ-PASSOS‚ D.; GODINO‚ A.; JOHNSON‚ A.K.; VIVAS‚ L.; ANTUNES-RODRIGUES‚ J. Dorsal raphe nuclei integrate allostatic information evoked by depletion-induced sodium ingestion. Experimental Neurology, v. 206, n. 1, p. 86-94, 2007.
REIS‚ W.L.; GIUSTI-PAIVA‚ A.; VENTURA‚ R.R.; MARGATHO‚ L.O.; GOMES‚ D.A.; ELIAS‚ L.L.K.; ANTUNES-RODRIGUES‚ J. Central nitric oxide blocks vasopressin‚ oxytocin and atrial natriuretic peptide release and antidiuretic and natriuretic responses induced by central angiotensin II in conscious rats. Experimental Physiology, v. 92, n. 5, p. 903-911, 2007.
RUGINSK‚ SG; OLIVEIRA‚ FRT; MARGATHO‚ LO; VIVAS‚ L.; ELIAS‚ LLK; ANTUNES-RODRIGUES‚ J. Glucocorticoid modulation of neuronal activity and hormone secretion induced by blood volume expansion. Experimental Neurology, v. 206, n. 2, p. 192-200, 2007.

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