Abstract
Collectively, the four subprojects that compose this proposal aim to reveal molecular mechanisms that regulate renal tubular function, elucidate how renal tubule dysfunction contributes to the pathophysiology of hypertension (HAS) and Chronic Kidney Disease (CKD) as well as to reveal the molecular mechanisms of antidiabetic agents along the nephron. The first sub-project aims to define the molecular bases of the translocation of the isoform 3 Na+/H+ (NHE3) between the microdomains of the microvilli of the proximal tubule, which is singularly important for maintaining effective circulating volume and blood pressure homeostasis. In the second subproject, we propose to define the molecular bases of the endogenous and pharmacological effects of glucagon like peptide-1 (GLP-1) on renal function, an incretin hormone and a therapeutical target for the treatment of Type 2 Diabetes Mellitus (DM2), both under physiological conditions and in experimental models of HAS and DM2. In the third subproject, we aim to establish a direct relationship between glucose homeostasis and regulation of salt balance and effective circulating volume. More specifically, we will test the hypothesis that NHE3 and the co-transporter Na+/glucose SGLT2 interact physically and functionally in the proximal tubule and that the renoprotective and cardioprotective effects of the SGLT2 inhibitor class of antidiabetic agents may also result from inhibition of NHE3. Finally, given the renoprotective actions of Dipeptidyl Peptidase IV (DPPIV) inhibitors, the fact that this enzyme is highly expressed in proximal tubule and our recent findings that suggest that DPPIV may be a biomarker of renal and cardiac dysfunction, we will investigate, in subproject 4, the association of DPPIV with the progression of renal and cardiovascular disease in patients with CKD. Additionally, we will implement our new experimental model of CKD to test the hypothesis that DPPIV inhibitors may have therapeutic efficacy in CKD; we will investigate the metabolic and enzymatic pathways that mediate these actions in renal proximal tubule cells. The knowledge gained through this project will provide a better understanding of the role of the kidneys in the maintenance of fluid, blood pressure and glucose homeostasis, covering different levels of complexity: molecular, cellular, tissue and integrated. Moreover, our findings may enable the development of new therapeutic procedures and to provide scientific bases for a better pharmacological management of patients with hypertension, DM2 and/or CKD. (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)
ARRUDA-JUNIOR, DANIEL F.;
MARTINS, FLAVIA L.;
SALLES, THIAGO ALMEIDA;
JENSEN, LEONARDO;
DARIOLLI, RAFAEL;
ANTONIO, EDNEI L.;
DOS SANTOS, LEONARDO;
CRAJOINAS, RENATO O.;
TUCCI, PAULO J. F.;
GOWDAK, LUIS HENRIQUE W.;
KRIEGER, JOSE EDUARDO;
PEREIRA, ALEXANDRE C.;
GIRARDI, ADRIANA C.
Postprandial increase in glucagon-like peptide-1 is blunted in severe heart failure.
Clinical Science,
v. 134,
n. 9,
p. 1081-1094,
MAY 2020.
Web of Science Citations: 0.
LOPES, NATHALIA R.;
MILANEZ, MAYCON I. O.;
MARTINS, BEATRIZ S.;
VEIGA, AMANDA C.;
FERREIRA, GIOVANNA R.;
GOMES, GUIOMAR N.;
GIRARDI, ADRIANA C.;
CARVALHO, POLLIANE M.;
NOGUEIRA, FERNANDO N.;
CAMPOS, RUY R.;
BERGAMASCHI, CASSIA T.;
NISHI, ERIKA E.
Afferent innervation of the ischemic kidney contributes to renal dysfunction in renovascular hypertensive rats.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY,
v. 472,
n. 3
JAN 2020.
Web of Science Citations: 1.
BERALDO, JULIANA ISA;
BENETTI, ACARIS;
BORGES-JUNIOR, FLAVIO ARAUJO;
ARRUDA-JUNIOR, DANIEL F.;
MARTINS, FLAVIA LETICIA;
JENSEN, LEONARDO;
DARIOLLI, RAFAEL;
SHIMIZU, MARIA HELOISA;
SEGURO, ANTONIO C.;
LUCHI, WEVERTON M.;
GIRARDI, ADRIANA C. C.
Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,
v. 20,
n. 8
APR 2 2019.
Web of Science Citations: 2.