Chung Hsien-Hui, Tseng Ching-Jiunn, Cheng Pei-Wen
Department of Pharmacy & Clinical Trial Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung City, 813414 Taiwan.
Preventive Medicine Program, Center for General Education, Chung Yuan Christian University, Taoyuan City, 320314 Taiwan.
J Diabetes Metab Disord. 2025 Jun 20;24(2):154. doi: 10.1007/s40200-025-01670-0. eCollection 2025 Dec.
Diabetic nephropathy (DN) contributes to the higher mortality, and Forxiga (dapagliflozin) effectively improves clinical outcomes of patients with type 2 diabetes. However, the effects of dapagliflozin on hyperglycemia-induced DN remain unclear.
Streptozotocin (STZ)-induced diabetic rats were used to investigate hyperglycemia-induced DN, and various parameters were evaluated for the oral administration of dapagliflozin (1.2 mg/kg/day) for 12 weeks in STZ-induced diabetic rats, including serum metabolic parameters, kidney morphology, renal glycogen, and renal collagen. Additionally, the biomedical mechanisms were further assessed by western blotting and immunohistochemistry staining.
Compared to normal rats, we observed significant changes in STZ-induced diabetic rats for metabolic parameters, renal pathogenesis, glycogen deposition, and collagen accumulation. However, the treatment with dapagliflozin for 12 weeks in STZ-induced diabetic rats significantly increased body weight, decreased plasma glucose, triglyceride, cholesterol, creatinine and blood urea nitrogen levels, and improved renal pathology, glycogen deposition, and collagen accumulation compared with STZ-induced diabetic rats. Additionally, hyperglycemia-induced DN further elevated renal expressions of N-cadherin, yes-associated protein (YAP), fibronectin, Myosin IIB, alpha-smooth muscle actin (α-SMA), CD11b, tumor necrosis factor alpha (TNF-α), caspase-3, acetyl superoxide dismutase 2 (AcSOD2) involved in renal epithelial-to-mesenchymal transition (EMT), fibrosis, inflammation, apoptosis, and oxidative stress, which were attenuated by dapagliflozin. Moreover, the higher expressions of renal glucose transporter 2 (GLUT2) and GLUT4, and lower expressions of renal peroxisome proliferator-activated receptor α (PPARα) in STZ-induced diabetic rats were reversed by dapagliflozin.
Dapagliflozin in STZ-induced diabetic rats exhibited anti-inflammation, anti-oxidation, EMT modulation, anti-apoptosis, and anti-fibrosis through the mediation of renal GLUT2, GLUT4, and PPARα expressions in the prevention of hyperglycemia-induced DN.
糖尿病肾病（DN）导致更高的死亡率，而安达唐（达格列净）可有效改善2型糖尿病患者的临床结局。然而，达格列净对高血糖诱导的DN的影响仍不清楚。
使用链脲佐菌素（STZ）诱导的糖尿病大鼠来研究高血糖诱导的DN，并对STZ诱导的糖尿病大鼠口服达格列净（1.2毫克/千克/天）12周后的各种参数进行评估，包括血清代谢参数、肾脏形态、肾糖原和肾胶原蛋白。此外，通过蛋白质免疫印迹法和免疫组织化学染色进一步评估其生物医学机制。
与正常大鼠相比，我们观察到STZ诱导的糖尿病大鼠在代谢参数、肾脏病变、糖原沉积和胶原蛋白积累方面有显著变化。然而，在STZ诱导的糖尿病大鼠中用达格列净治疗12周后，与STZ诱导的糖尿病大鼠相比，体重显著增加，血糖、甘油三酯、胆固醇、肌酐和血尿素氮水平降低，肾脏病理、糖原沉积和胶原蛋白积累得到改善。此外，高血糖诱导的DN进一步提高了参与肾上皮-间充质转化（EMT）、纤维化、炎症、细胞凋亡和氧化应激的N-钙黏蛋白、Yes相关蛋白（YAP）、纤连蛋白、肌球蛋白IIB、α-平滑肌肌动蛋白（α-SMA）、CD11b、肿瘤坏死因子α（TNF-α）、半胱天冬酶-3、乙酰超氧化物歧化酶2（AcSOD2）的肾表达，而达格列净可使其减弱。此外，达格列净逆转了STZ诱导的糖尿病大鼠中肾葡萄糖转运蛋白2（GLUT2）和GLUT4的较高表达以及肾过氧化物酶体增殖物激活受体α（PPARα）的较低表达。
在STZ诱导的糖尿病大鼠中，达格列净通过调节肾GLUT2、GLUT4和PPARα的表达，在预防高血糖诱导的DN中表现出抗炎、抗氧化、EMT调节、抗细胞凋亡和抗纤维化作用。
