title: Therapeutic potential of digitoflavone on diabetic nephropathy: nuclear factor erythroid 2-related factor 2-dependent anti-oxidant and anti-inflammatory effect.
abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a therapeutic target in many diseases, because it can induce antioxidant enzymes and other cytoprotective enzymes. Moreover, some Nrf2 activators have strong anti-inflammatory activities. Oxidative stress and inflammation are major components involved in the pathology of diabetic nephropathy. In the present study, we evaluated the Nrf2-dependent anti-oxidative and anti-inflammatory effects of digitoflavone in streptozotocin-induced diabetic nephropathy. The molecular mechanisms of digitoflavone were investigated in vitro using SV40-transformed mouse mesangial cells (SV40-Mes13). For the in vivo experiment, diabetes was induced in Nrf2+/+ and Nrf2-/- mice by STZ injection, and digitoflavone was administered 2 weeks after the STZ injection. Digitoflavone induced Nrf2 activation and decreased oxidative damage, inflammation, TGF-β1 expression, extracellular matrix protein expression, and mesangial cell hyperplasia in SV40-Mes13 cells. Digitoflavone-treated Nrf2+/+ mice, but not Nrf2-/- mice, showed attenuated common metabolic disorder symptoms, improved renal performance, minimized pathological alterations, and decreased oxidative damage, inflammatory gene expression, inflammatory cell infiltration, TGF-β1 expression, and extracellular matrix protein expression. Our results show that the anti-oxidative and anti-inflammatory effects of digitoflavone are mediated by Nrf2 activation and that digitoflavone can be used therapeutically to improve metabolic disorders and relieve renal damage induced by diabetes.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Teng
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Xueting
authors.initials: X
authors.lastname: Cai
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Wuguang
authors.initials: W
authors.lastname: Lu
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Yuanzhang
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Chunping
authors.initials: C
authors.lastname: Hu
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of  Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D047309:Flavones / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; D016326:Extracellular Matrix Proteins; D047309:Flavones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1