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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.

Ethnopharmacological Relevance: Ginkgo biloba extract (GBE) is an ancient Chinese phytomedicine which was used to treat various ailments including circulatory and demential disorders., Aim of the Study: To study GBE's protective effects on the glomerulosclerosis of diabetic nephropathy (DN) in rat mesangial cells by serum pharmacological methods., Materials and Methods: The cultured mesangial cells were divided into seven groups: normal, solvent control, high glucose, low dose of GBE serum, moderate dose of GBE serum, high dose of GBE serum, and GBE. The activities of cell antioxidases, type IV collagen and laminin, Smad2/3 and Smad7, and TGF-beta(1) mRNA were measured by methods of spectrophotometry, radioimmunoassay, immunocytochemistry, and RT-PCR, respectively., Results: The intensity of oxidative stress decreased in the GBE serum-treated groups in comparison with the high glucose group. In addition, the expression of Smad2/3 was greatly reduced, whereas Smad7 expression increased; type IV collagen, laminin and TGF-beta(1) mRNA levels were also diminished., Conclusion: These results suggest that GBE is protective agent against glomerulosclerosis in diabetic nephropathy of mesangial cells.