Abstract
Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic β-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-β, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, β-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.
Highlights
Diabetic nephropathy is a leading cause of chronic renal failure in western world [1]
Many studies have suggested that production of reactive oxygen species (ROS) is enhanced by hyperglycemia, and oxidative stress has been involved in the onset and progression of diabetic nephropathy [4]
We demonstrated that dapagliflozin, a novel Sodium glucose cotransporter 2 (SGLT2) inhibitor, suppressed hyperglycemia and restored bcell mass in diabetic db/db mice
Summary
Diabetic nephropathy is a leading cause of chronic renal failure in western world [1]. Emerging evidence suggests that inflammation is crucially contributed in the pathophysiology of diabetic nephropathy [3]. Many studies have suggested that production of reactive oxygen species (ROS) is enhanced by hyperglycemia, and oxidative stress has been involved in the onset and progression of diabetic nephropathy [4]. The regulation of inflammation and oxidative stress could be a potential target in the treatment of diabetic nephropathy. SGLT2 inhibitors, which can inhibit reabsorption of filtered glucose by blocking SGLT2, have been developed and proposed as novel hypoglycemic agents for treating patients with diabetes mellitus [7]. SGLT2 inhibitors are novel and promising drugs for treating type 2 diabetes patients, the effect of SGLT2 inhibition on diabetic nephropathy is unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
