Pleiotropic effects of antidiabetic agents and their pharmacological targets: renoprotective mechanisms beyond glycemic control

• Grant number: 21/14534-3
• Support Opportunities: Research Projects - Thematic Grants
• Start date: August 01, 2022
• End date: July 31, 2027
• 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
• Associated researchers: Alicia Ann Mcdonough ; Caio de Assis Moura Tavares ; Deborah Schechtman ; Eduardo Festozo Vicente ; Gustavo Henrique Goulart Trossini ; Luciano Ferreira Drager ; Lucília Maria Abreu Lessa Leite Lima ; Matthew Alexander Bailey ; RAVI NISTALA ; Weverton Machado Luchi
• Associated research grant(s): 24/02263-3 - Mechanisms underlying the inhibitory effect of gliflozins on NHE3 activity in the renal proximal tubule, AP.R; 24/02707-9 - Direct effects of SGLT2 inhibitors on cardiac cells exposed to uremic toxins, AP.R SPRINT
• Associated scholarship(s): 24/14474-9 - Mechanisms underlying the influence of SGLT2 inhibitors on distal convoluted tubule function, BE.PQ; 24/21069-3 - Isolation, identification, and validation of new renal tubular targets of glyflozins, BP.PD; 24/01750-8 - Synthesis, purification and characterization of FLAG peptides and analogues for immobilization of SGLT2 or iSGLT2 inhibitors for evaluation of cardiac and renal targets, BP.IC; + associated scholarships 23/13659-2 - Bidirectional interaction between SGLT2 and NHE3 in the renal proximal tubule, BP.IC; 23/16220-1 - Biochemical characterization of the NHE3-dipeptidyl peptidase 4 interaction in the renal proximal tubule, BP.TT; 23/03620-1 - Role of endogenous GLP-1 in protecting against salt-sensitive hypertension, BP.DD; 22/15827-7 - Impairment of postprandial GLP-1 bioavailability and renal GLP-1R activation in experimental hypertension: role of salt consumption, BP.IC; 23/00268-5 - Isolation, identification, and validation of new renal tubular targets of glyflozins, BP.PD; 22/14554-7 - Biochemical characterization of the NHE3-dipeptidyl peptidase 4 interaction in the renal proximal tubule, BP.TT - associated scholarships

Abstract

Altogether, the three subprojects that integrate this proposal aim to elucidate novel molecular mechanisms underlying the renal tubular actions of antidiabetic drugs and their pharmacological targets. The first subproject intends to explore the molecular basis of the renal tubular effects of gliflozins. More specifically, we will investigate the mechanisms by which the pharmacological and/or genetic inhibition of the Na+/glucose cotransporter (SGLT2) reduces the activity of the Na+/H+ exchanger isoform 3 (NHE3) in the proximal tubule. Additionally, we will test the hypothesis that gliflozins attenuate cisplatin-induced hypomagnesemia through the upregulation of membrane transporters and/or ion channels that mediate renal magnesium reabsorption. Furthermore, we will investigate whether the renal tubular actions of gliflozins may be mediated by targets other than SGLT2 and isolate, identify and validate these potential targets. In the second subproject, we intend to test the hypothesis that endogenous GLP-1 protects against salt-sensitive hypertension. We will also verify whether there is an association between impaired bioavailability of this incretin hormone and blood pressure levels and markers of activation of intrarenal neurohumoral systems in experimental models of arterial hypertension and hypertensive patients. In the third subproject, we propose to unravel the physiological and pathophysiological role of the enzyme dipeptidyl peptidase 4 (DPP4) in the renal proximal tubule. Studies will be conducted to understand the interplay between DPP4, NHE3, and angiotensin II under physiological conditions and the role of these interactions in the pathophysiology of arterial hypertension, considering the influence of sexual dimorphism. Additionally, proteomic and phosphoproteomic experiments will be carried out to identify differentially expressed and differentially phosphorylated proteins in the kidney of mice with specific deletion of DPP4 in the renal proximal tubule. The results obtained from this project may provide a better understanding of the role of the kidneys in the maintenance of volume, blood pressure, and glycemic homeostasis and how disturbances in renal tubular function can contribute to the pathophysiology of cardiovascular diseases. Furthermore, our findings may enable the development of new therapeutic strategies and provide a scientific basis for better pharmacological management of patients with cardiovascular, renal, and metabolic diseases. (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)

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)

BRAGA, GABRIELA CATAO D.; RIBEIRO-SILVA, JOAO CARLOS; BOARO, ANDREIA; MARTINS, FLAVIA LETICIA; MAUAD, THAIS; TAVARES, CAIO A. M.; TEIXEIRA, LISETE RIBEIRO; CARAMELLI, BRUNO; GIRARDI, ADRIANA C. C.. Restoring lung renin-angiotensin system balance through blood pressure control. Clinical Science, v. 139, n. 3, p. 13-pg., 2025-02-01. (20/05338-3, 21/14534-3)

GIRARDI, ADRIANA C. C.. Cellular and molecular mechanisms of antidiabetics beyond glycemic control. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 327, n. 1, p. 2-pg., 2024-07-27. (21/14534-3)

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)

GIRARDI, ADRIANA C. C.; POLIDORO, JULIANO Z.; CASTRO, PAULO C.; PIO-ABREU, ANDREA; NORONHA, IRENE L.; DRAGER, LUCIANO F.. Mechanisms of heart failure and chronic kidney disease protection by SGLT2 inhibitors in nondiabetic conditions. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 327, n. 3, p. 20-pg., 2024-09-17. (21/14534-3, 19/23496-8)