The multifaceted modulations by dapagliflozin in preventing hyperglycemia-induced diabetic nephropathy through glucose transporters and PPARα

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Dapagliflozin; Diabetic nephropathy; Glucose transporters; PPARα; STZ-induced diabetic rats.