SGLT2 Inhibitors in Cisplatin-Induced Hypomagnesemia: Molecular Mechanisms and Translational Approach

• Grant number: 25/12087-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2025
• End date: September 30, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Érika Fernandes de Jesus
• 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

Cisplatin is widely used in the treatment of solid tumors but frequently induces hypomagnesemia, which may range from asymptomatic cases to severe clinical manifestations such as tetany, seizures, and fatal arrhythmias. In many patients, oral or intravenous magnesium supplementation fails to restore normal serum levels due to ongoing renal losses. Recent evidence suggests that SGLT2 inhibitors may help correct hypomagnesemia. In studies from our group, dapagliflozin normalized serum magnesium and reduced magnesiuria in a patient treated with cisplatin. In a murine model, empagliflozin elicited similar effects, restoring serum magnesium levels, reducing urinary magnesium loss, reversing distal convoluted tubule (DCT) atrophy, and increasing TRPM6 expression and NaCl cotransporter (NCC) activity. Although these findings suggest that gliflozins influence DCT function, the molecular mechanisms involved remain incompletely understood. Moreover, clinical evidence supporting the therapeutic repositioning of SGLT2 inhibitors for treating hypomagnesemia is still lacking. This project aims to (1) elucidate the mechanisms by which SGLT2 inhibitors modulate DCT function and (2) test the hypothesis that gliflozins correct cisplatin-induced hypomagnesemia in humans while validating, in the clinical setting, the mechanisms identified in experimental models. To this end, we will employ in vivo and ex vivo approaches using male and female wild-type and SGLT2 knockout mice. Initially, we will perform molecular and functional characterization of the DCT, including analyses of NCC expression, phosphorylation, and activity, the CaSR-WNK4-SPAK signaling pathway, and TRPM6 abundance. Complementary studies using renal tubules in suspension will assess the effects of pathway-specific inhibitors and different SGLT2 inhibitors (empagliflozin, dapagliflozin, and canagliflozin). Subsequently, male mice will be treated with cisplatin for five weeks, and the effects of dapagliflozin will be compared with those of genetic SGLT2 deletion to determine whether the correction of hypomagnesemia is mediated by SGLT2 inhibition or off-target mechanisms. In parallel, we will conduct a prospective, open-label, 8-week interventional clinical study in patients with cisplatin-induced refractory hypomagnesemia. Serial measurements of serum magnesium and urinary extracellular vesicle biomarkers will be performed. The results of this project may provide mechanistic and clinical support for repositioning SGLT2 inhibitors as a novel therapeutic approach for refractory hypomagnesemia. (AU)