The Akt-FoxO3a-manganese superoxide dismutase pathway is involved in the regulation of oxidative stress in diabetic nephropathy

Abstract

New Findings: • What is the central question of this study? Oxidative stress is known to play an important role in the development and progression of diabetic nephropathy. However, the mechanism of overproduction of reactive oxygen species (ROS) in high-glucose conditions is not completely clear. • What is the main finding and its importance? We demonstrated that high-glucose concentrations induced excessive production of ROS and stimulated the phosphoinositide 3-kinase-Akt-FoxO3a signalling pathway via the upregulation of transforming growth factor-β1, resulting in phosphorylation and inactivation of FoxO3a and a reduction in the expression of its target gene, FoxO3a-dependent manganese superoxide dismutase, and then further excessive production of ROS. 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. © 2012 The Physiological Society.