Evaluation of renal hydroelectrolytic transport, oxidative stress and apoptosis in an experimental murine model of Tenofovir and Amphotericin B-induced nephrotoxicity: effects of Dapagliflozin treatment.

• Grant number: 24/09066-9
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2025
• End date: January 31, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Daniele Canale Cavicchioli
• Grantee: Daniele Canale Cavicchioli
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Ana Carolina de Bragança Viciana ; Rildo Aparecido Volpini

Abstract

Tenofovir disoproxil fumarate and amphotericin B have been associated with nephrotoxicity. Dapagliflozin, an SGLT2 inhibitor, is a novel hypoglycemic drug and its pleiotropic effects have beneficial effects on renal hemodynamics and reducing oxidative stress, inflammation and fibrosis. We aim to investigate whether dapagliflozin can be a therapeutic strategy to mitigate tenofovir and amphotericin B-induced nephrotoxicity. We will allocate Wistar rats to the following groups: Protocol 1 - Control (C), will receive a standard diet (SD) for 45 days; DAPA, will receive SD for 30 days and SD+dapagliflozin (20 mg/kg food) from the 31st to the 45th day; TDF, will receive SD+tenofovir (300 mg/kg food) for 45 days; TDF+DAPA, will receive SD+tenofovir for 30 days and SD+tenofovir+dapagliflozin from the 31st to the 45th day. Protocol 2 - C, will receive SD for 10 days; DAPA, will receive SD+dapagliflozin for 10 days; c-AmB, will receive SD+conventional amphotericin B (10 mg/kg/day by intraperitoneal injection [IP]) for 10 days; c-AmB+DAPA, will receive SD+dapagliflozin+conventional amphotericin B for 10 days; l-AmB, will receive SD+liposomal amphotericin B (10 mg/kg/day IP) for 10 days; l-AmB+DAPA, will receive SD+dapagliflozin+liposomal amphotericin B for 10 days. At the end of all the experimental protocols, we will evaluate: renal hemodynamics and morphology; protein expression of the renal transporters, the redox state and apoptosis-related elements; and inflammatory profile. It is plausible to suppose that dapagliflozin will exert protective effects in this experimental model, possibly due to its influence on the signaling pathways responsible for tenofovir and amphotericin B-induced nephrotoxicity. (AU)