Bidirectional interaction between SGLT2 and NHE3 in the renal proximal tubule

• Grant number: 23/13659-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Jennifer Nogueira Coelho
• 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 research grant: 21/14534-3 - Pleiotropic effects of antidiabetic agents and their pharmacological targets: renoprotective mechanisms beyond glycemic control, AP.TEM

Abstract

Na+/glucose cotransporter type 2 inhibitors (iSGLT2), also known as gliflozins, confer cardiorenal benefits, the precise mechanisms of which remain incompletely understood. Originally developed for treating type 2 diabetes mellitus (T2D), it was unexpectedly observed that these drugs reduce hospitalizations for heart failure (HF) and mortality from cardiovascular causes, irrespective of a T2D diagnosis. This has broadened their potential utility in HF treatment, regardless of its association with T2D. In response to this clinical evidence, numerous laboratories worldwide, including ours, have dedicated their efforts to unraveling the mechanisms underlying the cardiorenal benefits of gliflozins. One hypothesis posits a bidirectional interaction between SGLT2 and isoform 3 of the Na+/H+ exchanger (NHE3) in the renal proximal tubule, as iSGLT2 also inhibits NHE3. This functional and physical interaction could, at least partially, account for the observed effects of SGLT2 inhibitors on extracellular volume and blood pressure observed during gliflozin treatment. Furthermore, another avenue to explore is whether gliflozins may directly bind to NHE3. Given the above, this project aims to investigate whether gliflozins inhibit NHE3 simultaneously or solely through direct mechanisms (via NHE3 binding) or indirect mechanisms (via physical and functional interaction with SGLT2). Moreover, if the inhibition of NHE3 by gliflozins hinges on the interplay between these transporters, we will assess whether treatment with a specific NHE3 inhibitor can inhibit SGLT2 activity, thus confirming the existence of a bidirectional interaction. Understanding the mechanisms by which iSGLT2 reduces NHE3 activity will provide critical information to validate the existing clinical applications of gliflozins and potentially pave the way for future applicability of gliflozins in managing other chronic non-communicable diseases.