Direct effects of SGLT2 inhibitors on cardiac cells exposed to uremic toxins

• Grant number: 24/02707-9
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2024
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Adriana Castello Costa Girardi
• Principal researcher abroad: Leticia Prates Roma
• Institution abroad: Saarland University, Homburg, Germany
• 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 an increased risk of cardiovascular complications, driven by factors such as uremic toxins that contribute to reactive oxygen species generation and inflammation, ultimately leading to endothelial dysfunction, cardiac ischemia, cardiac remodeling, and arrhythmia. Despite increasing awareness of uremic toxins and their detrimental effects, current conventional dialysis regimens may not adequately remove them, necessitating the exploration of new therapies. Initially developed for type 2 diabetes (T2D) treatment, sodium-glucose cotransporter 2 inhibitors (SGLT2i), also referred to as gliflozins, have demonstrated significant cardiovascular and renal benefits in heart failure (HF) and CKD, irrespective of T2D, marking a significant advancement in cardio-renal medicine. Recent evidence from our research group shows that empagliflozin, a prominent SGLT2 inhibitor, may mitigate arrhythmogenic events in hypoxic cardiomyocytes, shedding light on a possible avenue for reducing arrhythmias induced by uremic toxins. Additionally, empagliflozin has been shown to potentially ameliorate endothelial dysfunction, a prevalent complication in CKD, through mechanisms involving antioxidant and anti-inflammatory effects. However, the direct effects of SGLT2i on cardiomyocytes and coronary artery endothelial cells exposed to uremic toxins remain unexplored. This collaborative effort between Dr. Adriana Girardi's laboratory and Dr. Leticia Prates Roma's laboratory aims to investigate whether SGLT2 inhibitors exert direct beneficial effects on cardiomyocytes and coronary artery endothelial cells exposed to uremic toxins, focusing on their potential to reduce oxidative stress. Through a multidisciplinary approach encompassing electrophysiological experiments and redox analysis using genetic sensors along with omic analyses, we anticipate that the results of this partnership will contribute to advancing the understanding of the pathophysiology and therapeutic strategies for cardiovascular complications in CKD, paving the way for future grant applications and fostering long-term scientific collaboration between institutions. (AU)