The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy.
The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy.
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作者：
Jiang T;Huang Z;Lin Y;Zhang Z;Fang D;Zhang DD
糖尿病肾病是肾功能衰竭的主要原因之一，肾功能衰竭伴随着活性氧（ROS）的产生。Nrf 2是控制维持细胞氧化还原稳态所必需的抗氧化反应的主要转录因子。在这里，我们报告了我们的研究结果，证明了Nrf 2对糖尿病肾病的保护作用。我们使用糖尿病肾病患者的人肾活检组织、Nrf 2 −/−小鼠链脲佐菌素诱导的糖尿病肾病模型和培养的人系膜细胞来探索Nrf 2对糖尿病肾病的保护作用。人糖尿病肾病患者的肾小球处于氧化应激状态，并且具有升高的Nrf 2水平。在动物研究中，Nrf 2被证明在改善链脲佐菌素诱导的肾损伤中至关重要。与Nrf 2 +/+小鼠相比，Nrf 2 −/−小鼠具有更高的ROS产生，并且遭受更大的氧化DNA损伤和肾损伤。在体内和体外系统中的机制研究表明，Nrf 2介导的对糖尿病肾病的保护作用至少部分是通过抑制转化生长因子-β1（TGF-β1）和减少细胞外基质的产生。在人肾小球系膜细胞中，高糖诱导ROS产生并激活Nrf 2及其下游基因的表达。此外，Nrf 2的激活或过表达以剂量依赖性方式抑制TGF-β1的启动子活性，而通过siRNA敲低Nrf 2则增强TGF-β1的转录和纤连蛋白的产生。这项工作清楚地表明了Nrf 2在糖尿病肾病中的保护作用，表明Nrf 2的饮食或治疗活化可用作预防或减缓糖尿病肾病进展的策略。
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. 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. 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. 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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影响因子：
7.4
作者：
Bakin, AV;Stourman, NV;Freeman, ML
通讯作者：
Freeman, ML
影响因子：
2.4
作者：
Jeong, Sun-Oh;Oh, Gi-Su;Ha, Hun-Yong;Koo, Bon Soon;Kim, Hak Sung;Kim, Youn-Chul;Kim, Eun-Cheol;Lee, Kang-Min;Chung, Hun-Taeg;Pae, Hyun-Ock
通讯作者：
Pae, Hyun-Ock
DOI：
10.1073/pnas.93.24.13943
发表时间：
1996-11-26
影响因子：
11.1
作者：
Chan, KM;Lu, RH;Kan, YW
通讯作者：
Kan, YW
影响因子：
3.8
作者：
Choi, Hoo-Kyun;Pokharel, Yuba Raj;Kang, Keon Wook
通讯作者：
Kang, Keon Wook
影响因子：
5
作者：
He, Xiaoqing;Kan, Hong;Ma, Qiang
通讯作者：
Ma, Qiang