Mechanisms underlying the influence of SGLT2 inhibitors on distal convoluted tubule function

• Grant number: 24/14474-9
• Support Opportunities: Scholarships abroad - Research
• Start date: February 01, 2025
• End date: April 30, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Adriana Castello Costa Girardi
• Host Investigator: James Arthur Mccormick
• 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
• Institution abroad: Oregon Health & Science University, United States
• Associated research grant: 21/14534-3 - Pleiotropic effects of antidiabetic agents and their pharmacological targets: renoprotective mechanisms beyond glycemic control, AP.TEM

Abstract

The distal convoluted tubule (DCT) is crucial for regulating blood pressure and magnesium homeostasis, highlighting its role in cardiovascular and kidney health. Both genetic and acquired disorders affecting the DCT can lead to renal sodium and magnesium loss. Hypomagnesemia, characterized by low serum magnesium levels, is also commonly observed in patients treated with the anti-tumor drug cisplatin, a condition that is difficult to manage. Emerging evidence suggests that SGLT2 inhibitors may correct hypomagnesemia. Ongoing studies from our laboratories have shown that the SGLT2 inhibitor dapagliflozin corrects hypomagnesemia in a cisplatin-treated patient, and empagliflozin similarly restores serum magnesium levels in cisplatin-treated rats. Empagliflozin mitigates renal magnesium wasting and reverses DCT atrophy while restoring expression of the magnesium channel TRPM6, the NaCl cotransporter (NCC), and phosphorylated NCC, and normalizing NCC activity. However, the mechanisms by which SGLT2 inhibitors influence DCT function remain unclear, and it is unknown if they restore serum magnesium levels through mechanisms other than DCT modulation. Therefore, this project aims to (i) test the hypothesis that the effects of SGLT2 inhibitors on NCC are indirect, potentially mediated by SGLT2 inhibitor-induced glycosuria leading to activation of the calcium-sensing receptor, and (ii) determine the role of the DCT in the restoration of serum magnesium by SGLT2 inhibitors in cisplatin-induced hypomagnesemia. To achieve these objectives, we will employ a combined approach of in vivo, ex vivo, and in vitro studies, including heterologous expression in HEK293 cells, kidney tubule suspension, and the use of a DCT-specific conditional knockout mouse model for TRPM6, respectively. As there is currently no effective treatment for hypomagnesemia resulting from renal magnesium wasting, SGLT2 inhibitors may present a promising solution. Thus, elucidating the mechanisms by which SGLT2 inhibitors correct hypomagnesemia is of critical importance.