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Molecular mechanisms of regulation of the proximal tubular function in hypertension

Grant number: 12/10146-0
Support type:Regular Research Grants
Duration: October 01, 2012 - September 30, 2014
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Adriana Castello Costa Girardi
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Gerhard Malnic
Associated grant(s):13/50384-0 - Collaborative effort to determine the molecular bases of the blood pressure lowering effects of the incretin hormone GLP-1, AP.R

Abstract

Hypertension affects more than one and a half billion people world-wide, however the precise causes of elevated blood pressure cannot be determined in most affected individuals. A compelling body of clinical and experimental evidences documents the importance of the kidney in the pathogenesis of essential hypertension and supports the notion that hypertension may be caused by a primary defect in renal function that impairs the kidneys' ability of maintaining Na+ balance. The renal proximal tubule plays a major role on regulation of extracellular volume, since it is responsible for the reabsorption of approximately two-thirds of the filtered sodium. The principal apical membrane mechanism for reabsorption of Na+ and secretion of H+ in this nephron segment is the Na+/H+ exchanger isoform 3, NHE3. Therefore, this NHE isoform plays a central role on volume homeostasis and systemic blood pressure control. By means of in vivo stationary microperfusion, we observed that NHE3 transport function is higher in the proximal tubule of spontaneously hypertensive rats (SHR) prior to the development hypertension and lower thereafter compared to the age-matched normotensive control Wistar Kyoto rats (WKY). This differential regulation of NHE3 activity is accompanied by changes in the phosphorylation of the transporter at PKA consensus site serine 552, located in the COOH-terminal region of NHE3, and by subcellular redistribution of the transporter among the proximal tubule apical membrane microdomains. Thus, the identification of the components of the signaling pathway that regulates NHE3 phosphorylation as well as that of its binding partners that mediate subcellular trafficking may be unraveled relevant mechanisms implicated in the pathophysiology of hypertension. Additionally, ongoing studies from our research group and from other laboratories have suggested that inhibition of NHE3-mediated sodium reabsorption in the renal proximal tubule may be one of the mechanisms by which incretin mimetic agents (GLP-1 analogs or GLP-1R agonists) and dipeptidyl peptidase IV (DPPIV) inhibitors significantly reduce blood pressure in patients and experimental models of hypertension, obesity and diabetes. This project will investigate the molecular mechanisms responsible for altered proximal tubular function in essential hypertension. The specific aims described in this proposal intend to address questions related not only to the pathogenesis of hypertension but also to the renal compensatory mechanisms that counteract blood pressure rising as well as to the deciphering of the molecular mechanisms underlying the antihypertensive actions of the incretin mimetic agents and DPPIV inhibitors. (AU)

Scientific publications (12)
(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)
VEIRAS, LUCIANA C.; GIRARDI, ADRIANA C. C.; CURRY, JOSHUA; PEI, LEI; RALPH, DONNA L.; TRAN, AN; CASTELO-BRANCO, REGIANE C.; PASTOR-SOLER, NURIA; ARRANZ, CRISTINA T.; YU, ALAN S. L.; MCDONOUGH, ALICIA A. Sexual Dimorphic Pattern of Renal Transporters and Electrolyte Homeostasis. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, v. 28, n. 12, p. 3504-3517, DEC 2017. Web of Science Citations: 34.
SAVIGNANO, FERNANDA A.; CRAJOINAS, RENATO O.; PACHECO, BRUNA P. M.; CAMPOS, LUCIENE C. G.; SHIMIZU, MARIA HELOISA M.; SEGURO, ANTONIO CARLOS; GIRARDI, ADRIANA C. C. Attenuated diuresis and natriuresis in response to glucagon-like peptide-1 in hypertensive rats are associated with lower expression of the glucagon-like peptide-1 receptor in the renal vasculature. European Journal of Pharmacology, v. 811, p. 38-47, SEP 15 2017. Web of Science Citations: 4.
CRAJOINAS, RENATO O.; POLIDORO, JULIANO Z.; CARNEIRO DE MORAIS, CARLA P. A.; CASTELO-BRANCO, REGIANE C.; GIRARDI, ADRIANA C. C. Angiotensin II counteracts the effects of cAMP/PKA on NHE3 activity and phosphorylation in proximal tubule cells. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 311, n. 5, p. C768-C776, NOV 1 2016. Web of Science Citations: 7.
FARAH, LIVIA X. S.; VALENTINI, VANESSA; PESSOA, THAISSA D.; MALNIC, GERHARD; MCDONOUGH, ALICIA A.; GIRARDI, ADRIANA C. C. The physiological role of glucagon-like peptide-1 in the regulation of renal function. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 310, n. 2, p. F123-F127, JAN 15 2016. Web of Science Citations: 33.
MACHADO BERGER, REBECA CALDEIRA; VASSALLO, PAULA FRIZERA; CRAJOINAS, RENATO DE OLIVEIRA; OLIVEIRA, MARILENE LUZIA; MARTINS, FLAVIA LETICIA; NOGUEIRA, BRENO VALENTIM; MOTTA-SANTOS, DAISY; ARAUJO, ISABELLA BINOTTI; FORECHI, LUDIMILA; COSTA GIRARDI, ADRIANA CASTELLO; SOUZA SANTOS, ROBSON AUGUSTO; MILL, JOSE GERALDO. Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats. PLoS One, v. 10, n. 10 OCT 23 2015. Web of Science Citations: 8.
CARNEIRO DE MORAIS, CARLA P.; POLIDORO, JULIANO Z.; RALPH, DONNA L.; PESSOA, THAISSA D.; OLIVEIRA-SOUZA, MARIA; BARAUNA, VALERIO G.; REBOUCAS, NANCY A.; MALNIC, GERHARD; MCDONOUGH, ALICIA A.; GIRARDI, ADRIANA C. C. Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 309, n. 8, p. C541-C550, OCT 15 2015. Web of Science Citations: 5.
LUCHI, WEVERTON M.; SHIMIZU, MARIA HELOISA M.; CANALE, DANIELE; GOIS, PEDRO HENRIQUE F.; DE BRAGANCA, ANA CAROLINA; VOLPINI, RILDO A.; GIRARDI, ADRIANA C. C.; SEGURO, ANTONIO C. Vitamin D deficiency is a potential risk factor for contrast-induced nephropathy. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, v. 309, n. 3, p. R215-R222, AUG 1 2015. Web of Science Citations: 10.
PONTES, ROBERTO B.; CRAJOINAS, RENATO O.; NISHI, ERIKA E.; OLIVEIRA-SALES, ELIZABETH B.; GIRARDI, ADRIANA C.; CAMPOS, RUY R.; BERGAMASCHI, CASSIA T. Renal nerve stimulation leads to the activation of the Na+/H+ exchanger isoform 3 via angiotensin II type I receptor. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 308, n. 8, p. F848-F856, APR 15 2015. Web of Science Citations: 21.
PESSOA, THAISSA DANTAS; GASTALHO CAMPOS, LUCIENE CRISTINA; CARRARO-LACROIX, LUCIENE; GIRARDI, ADRIANA C. C.; MALNIC, GERHARD. Functional Role of Glucose Metabolism, Osmotic Stress, and Sodium-Glucose Cotransporter Isoform-Mediated Transport on Na+/H+ Exchanger Isoform 3 Activity in the Renal Proximal Tubule. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, v. 25, n. 9, p. 2028-2039, SEP 2014. Web of Science Citations: 54.
CRAJOINAS, R. O.; PESSOA, T. D.; RODRIGUES, M. V.; MALNIC, G.; GIRARDI, A. C. C. Changes in the activity and expression of protein phosphatase-1 accompany the differential regulation of NHE3 before and after the onset of hypertension in spontaneously hypertensive rats. ACTA PHYSIOLOGICA, v. 211, n. 2, p. 395-408, JUN 2014. Web of Science Citations: 6.
DOS SANTOS, LEONARDO; SALLES, THIAGO A.; ARRUDA-JUNIOR, DANIEL F.; CAMPOS, LUCIENE C. G.; PEREIRA, ALEXANDRE C.; BARRETO, ANA LUIZA T.; ANTONIO, EDNEI L.; MANSUR, ALFREDO J.; TUCCI, PAULO J. F.; KRIEGER, JOSE E.; GIRARDI, ADRIANA C. C. Circulating Dipeptidyl Peptidase IV Activity Correlates With Cardiac Dysfunction in Human and Experimental Heart Failure. Circulation-Heart Failure, v. 6, n. 5, p. 1029-1038, SEP 2013. Web of Science Citations: 73.
INOUE, BRUNA H.; ARRUDA-JUNIOR, DANIEL F.; CAMPOS, LUCIENE C. G.; BARRETO, ANA LUIZA T.; RODRIGUES, MARILIZA V.; KRIEGER, JOSE EDUARDO; GIRARDI, ADRIANA C. C. Progression of microalbuminuria in SHR is associated with lower expression of critical components of the apical endocytic machinery in the renal proximal tubule. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 305, n. 2, p. F216-F226, JUL 2013. Web of Science Citations: 7.

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