The Protective Role of Nrf2 in Streptozotocin-Induced Diabetic Nephropathy
1Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona;
2Department of Pathology, Fudan University, Shanghai Medical College, Shanghai, China;
3Department of Pathology, Northwestern University, School of Medicine, Chicago, Illinois.
Corresponding author: Donna D. Zhang, Email: dzhang@pharmacy.arizona.edu.
Received September 10, 2009; Accepted January 7, 2010.
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Abstract
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-β1
(TGF-β1) 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-β1 in a
dose-dependent manner, whereas knockdown of Nrf2 by siRNA enhanced
TGF-β1 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.
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