Avaliação da função renal em camundongos submetidos à exposição crônica a dieta hiperpalatável e do efeito do tratamento com inibidor do cotransportador de sódio e glicose-2 (SGLT2)

Abstract

Obesity is directly associated with increased insulin resistance, which can elevate the risk of developing type 2 diabetes mellitus (T2DM), as well as the risk of heart disease, hypertension, and kidney dysfunctions. The accumulation of lipids leads to metabolic complications, conditions associated with a progressive decline in kidney function, increased pro-inflammatory mediators, and damage to renal structures, resulting in tubular injury, glomerular alterations, and hemodynamic overload. For controlling hyperglycemia in T2DM, a new class of antidiabetic drugs, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, has shown efficacy. These drugs reduce the reabsorption of glucose and sodium in the kidneys, lowering blood glucose levels and providing additional benefits, such as reducing oxidative stress, inflammation, and apoptosis in renal cells. In light of this, the aim of this study was to investigate the effects of a high-fat and high-sugar diet on the renal morphology and function of male and female mice. Additionally, we sought to evaluate the protective effect of dapagliflozin (an SGLT2 inhibitor) on glycemic status, lipid profile, renal function, and morphology, mimicking conditions of obesity and T2DM. Male and female C57Bl/6 mice, aged 4 weeks, were used (CEUA: #71/2023). The animals were divided into two groups: one was maintained on a high-fat and high-sugar diet, while the other followed a control diet (AIN93G) for a period of 12 weeks to simulate conditions of obesity and T2DM. After the first 8 weeks of the diet, the mice began treatment with dapagliflozin (DAPA, 1 mg/kg/day) for a period of 4 weeks. The mice were euthanized for the analysis of renal function and morphology. The results were analyzed by two-way ANOVA followed by Tukey’s post-hoc test, with significance set at P<0.05 between groups. Male HSB mice showed significant weight gain starting from the 5th week of the diet, which persisted until the 12th week. Female HSB mice gained weight starting from the 6th week, which also persisted until the 12th week. Furthermore, male HSB mice exhibited metabolic alterations characterized by hyperglycemia and impaired glucose tolerance, whereas these changes were not observed in females. DAPA treatment was not effective in reducing body weight over the course of treatment; however, it reduced hyperglycemia and restored glucose tolerance in male HSB mice. Renal function results showed a significant increase in proteinuria in male HSB mice, indicating kidney injury. The elevated levels of GGT and LDH in the urine further reinforced the presence of tubular damage. DAPA treatment was effective in reducing these markers, suggesting a possible protective effect on renal tubular function in mice subjected to a hyperpalatable diet, contributing to the preservation of the functional integrity of the kidneys. Structurally, the kidneys of male HSB mice showed damage, characterized by the presence of vacuolation, increased interstitial cells, and decreased tubular cells. Notably, DAPA treatment was able to reverse these alterations. Increased inflammation was observed with elevated IL-1β levels, associated with increased lipotoxicity, evidenced by elevated triglycerides in the renal tissue of male HSB mice. Therefore, our work reveals a distinct pattern of responses between males and females, highlighting a complex interaction between diet, weight gain, and renal function. However, further studies are needed to understand the effects of the HSB diet in females.