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Mechanisms mediating the natriuretic and antihypertensive effects of SGLT2 inhibition

Grant number: 19/12315-2
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): July 01, 2019
Effective date (End): June 30, 2020
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Thiago Matheus Santos Rios
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
Associated research grant:16/22140-7 - Molecular bases of renal tubular function and dysfunction, AP.TEM

Abstract

The Na+/glucose cotransporter SGLT2 reabsorbs most of the glucose filtered by the kidneys. SGLT2 inhibitors, recently approved as new antidiabetic drugs, reduce reabsorption of glucose by the kidneys, thereby reducing blood glucose levels. Data from clinical studies indicate that patients with type 2 diabetes mellitus treated with SGLT2 inhibitors display a consistent decrease in systolic blood pressure of 3-8 mmHg. This antihypertensive effect may be due, at least in part, to the osmotic effect and body weight reduction induced by inhibition of SGLT2, however, these correlations demand lines with evidence with greater strength of association. On the other hand, experimental studies conducted by our research group suggest that SGLT2 and the isoform 3 of the Na+/H+ exchanger (NHE3) may interact functionally, so that inhibition of SGLT2 may also inhibit NHE3 activity in the proximal tubule. During the first year of the development of this project, we validated this hypothesis. More specifically, we demonstrated that long-term systemic administration of the inhibitor of SGLT2 empagliflozin increases natriuretic and inhibits NHE3 activity in tubule proximal of normotensive and hypertensive rats. In addition, we observed that treatment with empagliflozin reduces the blood pressure levels of spontaneously hypertensive rats at least in part by inhibiting NHE3 activity. In this second year, we intend to investigate the mechanisms mediating the inhibitory action of empagliflozin on NHE3. We also intend to investigate whether inhibition of SGLT2 alters the expression of other sodium transporters present in the apical membrane of the renal tubule. The results from this project can contribute to establishing the cardiovascular benefits of treatment with SGLT2 inhibitors.