title: Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice.
abstract: It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, we investigated the effect of dapagliflozin on early-stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight-week-old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin-treated group compared with those in the insulin-treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose-dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia-induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.
authors.affiliation: Departments of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hatanaka
authors.affiliation: Departments of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan; Department of Diabetic Nephropathy Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.affiliation: Departments of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan; Department of Neurochemistry Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tachibana
authors.affiliation: Departments of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Eguchi
authors.affiliation: Departments of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan; Department of Diabetic Nephropathy Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Neurochemistry Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Neurochemistry Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Takei
authors.affiliation: Departments of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.affiliation: Departments of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
keywords: Diabetic nephropathy; SGLT2 inhibitor; hyperglycemia; oxidative stress; urinary albumin excretion