Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Department of Anatomy and Embryology, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt.
Fundam Clin Pharmacol. 2022 Apr;36(2):306-323. doi: 10.1111/fcp.12721. Epub 2021 Sep 10.
The current study was conducted to investigate the nephroprotective effects of vildagliptin-metformin combination in an experimental model of fructose/salt-induced metabolic syndrome (MetS). A major aim was to evaluate the potential capacity of vitamin D3 to potentiate the pleiotropic nephroprotective effects of vildagliptin-metformin combination. MetS was induced in adult male Wistar rats by adding fructose (10%) to everyday drinking water and salt (3%) to the diet for 6 weeks. Along with the same concentrations of fructose/salt feeding, MetS rats were then treated orally with either vildagliptin (10 mg/kg/day)-metformin (200 mg/kg/day) combination, vitamin D3 (10 μg/kg/day), or the triple therapy for a further 6 weeks. The incidence of MetS was confirmed 6 weeks after fructose/salt consumption, when the rats exhibited significant weight gain, dyslipidemia, hyperuricemia, insulin resistance, hyperinsulinemia, and impaired glucose tolerance. At the end of the 12-week experimental period, MetS rats displayed significantly deteriorated renal function, enhanced intrarenal oxidative stress and inflammation together with exaggerated renal histopathological damages and interstitial fibrosis. The study has corroborated antioxidant, anti-inflammatory, and antifibrotic effects of vildagliptin-metformin combination, vitamin D3, and the triple collaborative therapy, conferring renoprotection in the setting of MetS. Due attention has been paid to the crucial role of dipeptidyl peptidase-4 inhibition and sirtuin-1/5' adenosine monophosphate-activated protein kinase activation as novel therapeutic targets to optimize renoprotection. The apparent potentiating effect, evoked upon coadministration of vitamin D3 with vildagliptin-metformin combination, may provide a cornerstone for further clinical investigations.
本研究旨在探讨维格列汀-二甲双胍联合治疗在果糖/盐诱导的代谢综合征（MetS）实验模型中的肾脏保护作用。主要目的是评估维生素 D3 增强维格列汀-二甲双胍联合治疗的多种肾脏保护作用的潜在能力。成年雄性 Wistar 大鼠通过在日常饮用水中添加果糖（10%）和饮食中添加盐（3%）6 周来诱导 MetS。在给予相同浓度的果糖/盐喂养的同时，MetS 大鼠随后经口给予维格列汀（10mg/kg/天）-二甲双胍（200mg/kg/天）联合治疗、维生素 D3（10μg/kg/天）或三联疗法，进一步治疗 6 周。在果糖/盐摄入 6 周后，确认 MetS 的发生，此时大鼠表现出明显的体重增加、血脂异常、高尿酸血症、胰岛素抵抗、高胰岛素血症和糖耐量受损。在 12 周的实验期结束时，MetS 大鼠的肾功能明显恶化，肾内氧化应激和炎症增强，伴有明显的肾脏组织病理学损伤和间质纤维化。该研究证实了维格列汀-二甲双胍联合治疗、维生素 D3 和三联协同治疗的抗氧化、抗炎和抗纤维化作用，在 MetS 环境中具有肾脏保护作用。本研究还关注了二肽基肽酶-4 抑制和沉默信息调节因子 1/5' 腺苷单磷酸激活蛋白激酶激活作为优化肾脏保护作用的新治疗靶点的关键作用。维生素 D3 与维格列汀-二甲双胍联合治疗联合给药时的明显增强作用可能为进一步的临床研究提供基础。
