Mechanisms Underlying the Cardiovascular Benefits of SGLT2 Inhibitors in Chronic Kidney Disease: On-Target and Off-Target Effects

• Grant number: 25/14420-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2026
• End date: December 31, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Flavia Leticia Martins
• 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

Patients with chronic kidney disease (CKD) face a high risk of cardiovascular complications due to factors such as uremic toxins, which contribute to the generation of reactive oxygen species and inflammation, leading to endothelial dysfunction, cardiac ischemia, cardiac remodeling, and arrhythmias. Despite the growing recognition of these harmful effects, traditional dialysis methods often fail to effectively remove these toxins, highlighting the need for new therapeutic strategies. Initially developed for the treatment of type 2 diabetes (T2D), sodium-glucose cotransporter-2 inhibitors (SGLT2i), also known as gliflozins, have demonstrated significant cardiovascular and renal benefits in patients with heart failure (HF) and CKD, regardless of the presence of T2D, representing an important advancement in cardiorenal medicine. However, the potential cardiovascular benefits of SGLT2 inhibitors in uremic cardiomyopathy, as well as their underlying mechanisms, are not yet fully understood. This project aims to test the hypothesis that SGLT2 inhibitors improve cardiac and vascular function in mice with CKD induced by an adenine-containing diet, at least in part due to the reduction of local oxidative stress in these organs. Given the known actions of gliflozins, both through the inhibition of SGLT2 in the renal proximal tubule (on-target effects) and through binding to other targets in cells that do not express this transporter (off-target effects), we will use SGLT2 knockout mice treated or not with empagliflozin. This approach aims to investigate whether the administration of SGLT2 inhibitors in SGLT2 knockout mice (on-target + off-target) provides superior cardiovascular benefits and reductions in cellular oxidative stress compared to the observed benefits in knockout mice (on-target). In addition to in vivo studies, we will investigate in vitro whether SGLT2 inhibitors exert direct beneficial effects on isolated neonatal rat cardiomyocytes and human coronary artery endothelial cells exposed to uremic toxins, focusing on their ability to reduce oxidative stress. Through a multidisciplinary approach that includes classical experiments for the evaluation of cardiac and vascular function, electrophysiological analyses, redox analysis with genetic sensors, and omics analyses, we expect the results of this project to contribute to advancing the understanding of the pathophysiology and therapeutic strategies for cardiovascular complications in CKD. (AU)