Evaluation of the selective SGLT-2 inhibitor dapagliflozin as an alternative treatment on renal impairment in a nephrectomy model 5/6 associated with Obesity

• Grant number: 23/06387-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): September 01, 2023
• Effective date (End): August 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Rildo Aparecido Volpini
• Grantee: Desiree Rita Denelle Bernardo
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Obesity is a chronic disease commonly characterized by the accumulation of body fat and considered a worldwide epidemic conditioned by lifestyle habits. Renal changes associated with obesity are related to hemodynamic changes, mainly glomerular hyperperfusion, increased filtration fraction and proteinuria. In addition, structural changes such as increased renal weight, glomerulomegaly, thickening of the glomerular basement membrane, mesangial matrix expansion and podocyte dysfunction are observed in the course of the main renal pathologies associated with obesity. Lately, there has been a great interest in studying the influence of risk factors such as hypovitaminosis D and obesity on the progression of kidney disease. Furthermore, the alternative use of SGLT-2 inhibitors has been offering new perspectives and strategies for the treatment of kidney disease, regardless of their glucosuric effects. The present study aims to evaluate the effects of the selective SGLT-2 inhibitor dapagliflozin as an alternative treatment on renal impairment in an obesity-associated 5/6 nephrectomy (Nx) model. Male wistar rats (180-200 g) will be submitted to Nx surgery on day 40 day and followed up until the day 100. Dapagliflozin (50 mg/kg diet) will be administered from the 41st day. The animals will be divided into four groups according to the diet received: standard (N+P); hyperlipidic (N+H); standard+dapagliflozin (N+P+G); and hyperlipidic+dapagliflozin (N+H+G). At the end of the protocol we will perform anthropometric measurements, assessment of inulin clearance, renal hemodynamic studies and biochemistry in plasma (electrolytes, cytokines, hormones) and urine (electrolytes) samples. We will use kidney tissue (frozen or fixed) for protein, gene and immunohistochemical expression studies to quantify cytokines, markers of inflammation and phenotypic change, extracellular matrix proteins and histomorphometric evaluation. Our results will allow us to evaluate whether the alternative use of dapagliflozin will exert renoprotective effects in an obesity model associated with Nx. (AU)