The Protective Role of Nrf2 in Streptozotocin-Induced Diabetic Nephropathy

OBJECTIVE-Diabetic nephropathy is one of the major causes of renal failure, which is accompanied by the production of reactive oxygen species (ROS). Nrf2 is the primary transcription factor that controls the antioxidant response essential for maintaining cellular redox homeostasis. Here, we report our findings demonstrating a protective role of Nrf2 against diabetic nephropathy. RESEARCH DESIGN AND METHODS-We explore the protective role of Nrf2 against diabetic nephropathy using human kidney biopsy tissues from diabetic nephropathy patients, a streptozotocin-induced diabetic nephropathy model in Nrf2(-/-) mice, and cultured human mesangial cells. RESULTS-The glomeruli of human diabetic nephropathy patients were under oxidative stress and had elevated Nrf2 levels. In the animal study, Nrf2 was demonstrated to be crucial in ameliorating streptozotocin-induced renal damage. This is evident by Nrf2(-/-) mice having higher ROS production and suffering from greater oxidative DNA damage and renal injury compared with Nrf2(+/+) mice. Mechanistic studies in both in vivo and in vitro systems showed that the Nrf2-mediated protection against diabetic nephropathy is, at least, partially through inhibition of transforming growth factor-beta 1 (TGF-beta 1) and reduction of extracellular matrix production. In human renal mesangial cells, high glucose induced ROS production and activated expression of Nrf2 and its downstream genes. Furthermore, activation or overexpression of Nrf2 inhibited the promoter activity of TGF-beta 1 in a dose-dependent manner, whereas knockdown of Nrf2 by siRNA enhanced TGF-beta 1 transcription and fibronectin production. CONCLUSIONS-This work clearly indicates a protective role of Nrf2 in diabetic nephropathy, suggesting that dietary or therapeutic activation of Nrf2 could be used as a strategy to prevent or slow down the progression of diabetic nephropathy. Diabetes 59:850-860, 2010