Molecular bases of renal tubular function and dysfunction

• Grant number: 16/22140-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: June 01, 2017
• End date: July 31, 2022
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Adriana Castello Costa Girardi
• Host 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
• City of the host institution: São Paulo
• Associated researchers: Alexandre da Costa Pereira ; Alicia Ann McDonough ; Gerhard Malnic ; Oscar Lorenzo ; Silvia Maria de Oliveira Titan ; Weverton Machado Luchi
• Associated research grant(s): 20/05338-3 - Modulation of ACE2 in experimental hypertension and in response to treatment with ACE inhibitors and ARBs: potential implications for COVID-19 severity and therapeutic targets, AP.R; 19/23521-2 - Interplay between dipeptidyl peptidase-4 and Angiotensin II on renal proximal tubule NHE3-mediated sodium reabsorption and blood pressure regulation, AP.R SPRINT
• Associated scholarship(s): 21/14045-2 - Role of motor protein myosin VI in subcellular distribution of NHE3 in the renal proximal tubule, BP.IC; 19/11944-6 - Interaction between dipeptidyl peptidase IV and the intra-renal renin angiotensin system on blood pressure levels and sodium transport throughout the nephron, BP.DR; 20/07371-8 - Modulation of ACE2 in experimental hypertension and in response to treatment with ACE inhibitors and ARBs: potential implications for COVID-19 severity and therapeutic targets, BP.IC; + associated scholarships 19/09860-9 - Potential biomarker and therapeutic target of dipeptidyl peptidase IV in Chronic Kidney Disease, BP.DR; 19/12315-2 - Mechanisms mediating the natriuretic and antihypertensive effects of SGLT2 inhibition, BP.IC; 18/05431-3 - Mechanisms responsible for cardioprotective effects of SGLT2 inhibitors: molecular, functional and translational approach, BP.PD; 18/01235-5 - Role of myosin IIA motor protein in NHE3-mediated sodium reabsorption in renal proximal tubule, BP.PD; 17/13104-0 - Role of glucagon-like peptide-1 in the pathophysiology of hypertension, BP.MS - associated scholarships

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

(21)

(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)

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.; et al. 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. (13/10619-8, 16/22140-7)

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.; et al. 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. (17/12383-2, 15/23858-6, 18/02671-3, 16/22140-7)

DOS SANTOS, DANUBIA SILVA; POLIDORO, JULIANO Z.; BORGES-JUNIOR, FLAVIO A.; GIRARDI, ADRIANA C. C.. Cardioprotection conferred by sodium-glucose cotransporter 2 inhibitors: a renal proximal tubule perspective. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 318, n. 2, p. C328-C336, FEB 2020. (16/22140-7)

MARTINS, FLAVIA L.; TAVARES, CAIO A. M.; MALAGRINO, PAMELLA A.; RENTZ, THIAGO; BENETTI, ACARIS; RIOS, THIAGO M. S.; PEREIRA, GABRIEL M. D.; CARAMELLI, BRUNO; TEIXEIRA, SAMANTHA K.; KRIEGER, JOSE E.; et al. Sex differences in the lung ACE/ACE2 balance in hypertensive rats. BIOSCIENCE REPORTS, v. 41, n. 12, DEC 2021. (20/05338-3, 16/22140-7)

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.; et al. Postprandial increase in glucagon-like peptide-1 is blunted in severe heart failure. Clinical Science, v. 134, n. 9, p. 1081-1094, MAY 2020. (13/10619-8, 13/17368-0, 16/22140-7)

POLIDORO, JULIANO Z.; LUCHI, WEVERTON M.; SEGURO, ANTONIO CARLOS; MALNIC, GERHARD; GIRARDI, ADRIANA C. C.. Paracrine and endocrine regulation of renal K+ secretion. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 322, n. 3, p. 18-pg., 2022-03-01. (20/05338-3, 16/22140-7)

TAVARES, CAIO A. M.; BAILEY, MATTHEW A.; GIRARDI, ADRIANA C. C.. Biological Context Linking Hypertension and Higher Risk for COVID-19 Severity. FRONTIERS IN PHYSIOLOGY, v. 11, NOV 19 2020. (20/05338-3, 16/22140-7)

RIBEIRO-SILVA, JOAO CARLOS; TAVARES, CAIO A. M.; GIRARDI, ADRIANA C. C.. The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: A mini-review of the mechanisms. CURRENT OPINION IN PHARMACOLOGY, v. 69, p. 9-pg., 2023-02-28. (16/22140-7, 21/14534-3)

FONTES, MILENE T.; ARRUDA-JUNIOR, DANIEL F.; DOS SANTOS, DANUBIA SILVA; RIBEIRO-SILVA, JOAO CARLOS; ANTO, EDINEI L.; TUCCI, PAULO F. J.; ROSSONI, LUCIANA V.; GIRARDI, ADRIANA C. C.. Dipeptidyl peptidase 4 inhibition rescues PKA-eNOS signaling and suppresses aortic hypercontractility in male rats with heart failure. Life Sciences, v. 323, p. 10-pg., 2023-04-21. (14/17135-9, 16/08907-3, 14/20303-0, 18/05431-3, 16/22140-7, 13/10619-8)

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.; et al. 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, p. 18-pg., 2019-04-02. (16/22140-7, 13/10619-8)

CORREA, JOSE WILSON N.; BOARO, KAROLINE R.; SENE, LETICIA B.; POLIDORO, JULIANO Z.; SALLES, THIAGO A.; MARTINS, FLAVIA L.; BENDHACK, LUSIANE M.; GIRARDI, ADRIANA C. C.. Antiproteinuric and Hyperkalemic Mechanisms Activated by Dual Versus Single Blockade of the RAS in Renovascular Hypertensive Rats. FRONTIERS IN PHYSIOLOGY, v. 12, JUN 9 2021. (16/22140-7)

DOS ANJOS VIEIRA, JOAO VITOR; MARQUES, VINICIUS BERMOND; VIEIRA, LUIZA VALLI; CRAJOINAS, RENATO DE OLIVEIRA; MASSOLA SHIMIZU, MARIA HELOISA; SEGURO, ANTONIO CARLOS; WEITZEL DIAS CARNEIRO, MARIA TEREZA; COSTA GIRARDI, ADRIANA CASTELLO; VASSALLO, DALTON VALENTIM; DOS SANTOS, LEONARDO. Changes in the renal function after acute mercuric chloride exposure in the rat are associated with renal vascular endothelial dysfunction and proximal tubule NHE3 inhibition. Toxicology Letters, v. 341, p. 23-32, MAY 1 2021. (16/22140-7)

MARTINS, FLAVIA L.; BAILEY, MATTHEW A.; GIRARDI, ADRIANA C. C.. Endogenous Activation of Glucagon-Like Peptide-1 Receptor Contributes to Blood Pressure Control Role of Proximal Tubule Na+/H(+)Exchanger Isoform 3, Renal Angiotensin II, and Insulin Sensitivity. Hypertension, v. 76, n. 3, p. 839-848, SEP 2020. (16/22140-7)

POLIDORO, JULIANO ZEQUINI; REBOUCAS, NANCY AMARAL; GIRARDI, ADRIANA CASTELLO COSTA. The Angiotensin II Type 1 Receptor-Associated Protein Attenuates Angiotensin II-Mediated Inhibition of the Renal Outer Medullary Potassium Channel in Collecting Duct Cells. FRONTIERS IN PHYSIOLOGY, v. 12, MAY 14 2021. (16/22140-7, 13/11093-0)

LUCHI, WEVERTON M.; CRAJOINAS, RENATO O.; MARTINS, FLAVIA L.; CASTRO, PAULO DE C.; VENTURINI, GABRIELA; SEGURO, ANTONIO C.; GIRARDI, ADRIANA C. C.. High blood pressure induced by vitamin D deficiency is associated with renal overexpression and hyperphosphorylation of Na+-K+-2Cl-cotransporter type 2. Journal of Hypertension, v. 39, n. 5, p. 880-891, MAY 2021. (16/22140-7)

BENETTI, ACARIS; MARTINS, FLAVIA LETICIA; SENE, LETICIA BARROS; SHIMIZU, MARIA HELOISA M.; SEGURO, ANTONIO C.; LUCHI, WEVERTON M.; GIRARDI, ADRIANA C. C.. Urinary DPP4 correlates with renal dysfunction, and DPP4 inhibition protects against the reduction in megalin and podocin expression in experimental CKD. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 320, n. 3, p. F285-F296, MAR 2021. (16/22140-7)

ARRUDA-JUNIOR, DANIEL F.; SALLES, THIAGO A.; MARTINS, FLAVIA L.; ANTONIO, EDNEI L.; TUCCI, PAULO J. F.; GOWDAK, LUIS HENRIQUE W.; TAVARES, CAIO A. M.; GIRARDI, ADRIANA C.. Unraveling the interplay between dipeptidyl peptidase 4 and the renin-angiotensin system in heart failure. Life Sciences, v. 305, p. 11-pg., 2022-07-06. (13/10619-8, 16/22140-7)

CRAJOINAS, RENATO O.; POLIDORO, JULIANO Z.; GIRARDI, ADRIANA C. C.. The potential role of myosin motor proteins in mediating the subcellular distribution of NHE3 in the renal proximal tubule. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 316, n. 5, p. F986-F992, MAY 2019. (16/22140-7)

CASTRO, PAULO C.; SANTOS-RIOS, THIAGO M.; MARTINS, FLAVIA L.; CRAJOINAS, RENATO O.; CAETANO, MARCOS V.; LESSA, LUCILIA M. A.; LUCHI, WEVERTON M.; MCCORMICK, JAMES A.; GIRARDI, ADRIANA C. C.. Renal upregulation of NCC counteracts empagliflozin-mediated NHE3 inhibition in normotensive but not in hypertensive male rat. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 326, n. 6, p. 17-pg., 2024-06-01. (21/14534-3, 16/22140-7)

COELHO, PAULO; SANTOS-RIOS, THIAGO; MARTINS, FLAVIA; CRAJOINAS, RENATO; CAETANO, MARCOS. Renal upregulation of NCC counteracts empagliflozin-mediated NHE3 inhibition in normotensive but not in hypertensive rats. PHYSIOLOGY, v. 39, p. 1-pg., 2024-05-01. (21/14534-3, 16/22140-7)

BENETTI, ACARIS; RIBEIRO-SILVA, JOAO CARLOS; GOMEZ, LUZ M.; TAVARES, CAIO A. M.; BENSENOR, ISABELA J.; LOTUFO, PAULO A.; TITAN, SILVIA M. O.; GIRARDI, ADRIANA C. C.. Association of urinary dipeptidyl peptidase 4 activity with clinical outcomes in people with chronic kidney disease. SCIENTIFIC REPORTS, v. 15, n. 1, p. 10-pg., 2025-07-02. (21/14534-3, 16/22140-7, 11/17341-0)