title: The Akt-FoxO3a-manganese superoxide dismutase pathway is involved in the regulation of oxidative stress in diabetic nephropathy.
abstract: Oxidative stress has been shown to play an important role in the development and progression of diabetic nephropathy, and the formation of reactive oxygen species (ROS) is a direct consequence of hyperglycaemia. We hypothesized that hyperglycaemia-induced ROS can activate the transforming growth factor-β1 (TGF-β1)-phosphoinositide 3-kinase (PI3K)-Akt-FoxO3a signalling pathway, negatively regulating expression of manganese superoxide dismutase (MnSOD), which promotes excessive ROS generation and accelerates the pathological process of diabetic nephropathy. In vitro, in rat mesangial cells, high glucose (30 mmol l(-1)), but not equimolar mannitol, stimulated ROS production, upregulated the levels of TGF-β1, increased the phosphorylated Akt/total Akt and phosphorylated FoxO3a/total FoxO3a protein ratios, altered the subcellular localization of FoxO3a and reduced the levels of MnSOD expression. These high-glucose-induced changes further promoted the generation of ROS. In vivo, in db/db mice treated with an inhibitor of TGF-β1 (SB431542) or PI3K (LY294002), the levels of phosphorylated Akt and phosphorylated FoxO3a in the kidney cortices were decreased, the level of MnSOD expression was increased and the level of the lipid peroxidation end-product, malondialdehyde, was reduced. We conclude that overproduction of ROS induced by a high glucose concentration decreases the expression of MnSOD via the PI3K-Akt-FoxO3a pathway and further aggravates oxidative stress in diabetic nephropathy.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Xuzhou Medical College, Xuzhou, Jiangsu 221004, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lu
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Zhai
authors.forename: Qian
authors.initials: Q
authors.lastname: Cheng
authors.forename: Yaowu
authors.initials: Y
authors.lastname: Liu
authors.forename: Xing
authors.initials: X
authors.lastname: Gao
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Wei
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Yin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D013482:Superoxide Dismutase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose