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Nrf2 在链脲佐菌素诱导的糖尿病肾病中的保护作用。

The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy.

机构信息

Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA.

出版信息

Diabetes. 2010 Apr;59(4):850-60. doi: 10.2337/db09-1342. Epub 2010 Jan 26.

DOI:10.2337/db09-1342
PMID:20103708
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2844833/
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-beta1 (TGF-beta1) 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-beta1 in a dose-dependent manner, whereas knockdown of Nrf2 by siRNA enhanced TGF-beta1 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.

摘要

目的

糖尿病肾病是肾衰竭的主要原因之一，其伴随着活性氧（ROS）的产生。Nrf2 是控制维持细胞氧化还原平衡所必需的抗氧化反应的主要转录因子。在这里，我们报告了我们的发现，表明 Nrf2 对糖尿病肾病具有保护作用。

研究设计和方法

我们使用来自糖尿病肾病患者的人肾活检组织、链脲佐菌素诱导的 Nrf2(-/-) 小鼠糖尿病肾病模型和培养的人肾小球系膜细胞来探索 Nrf2 对糖尿病肾病的保护作用。

结果

人类糖尿病肾病患者的肾小球处于氧化应激状态，Nrf2 水平升高。在动物研究中，Nrf2 被证明在改善链脲佐菌素诱导的肾脏损伤中至关重要。这可以通过 Nrf2(-/-) 小鼠比 Nrf2(+/+) 小鼠产生更高的 ROS、遭受更大的氧化 DNA 损伤和肾脏损伤来证明。体内和体外系统的机制研究表明，Nrf2 介导的对糖尿病肾病的保护至少部分是通过抑制转化生长因子-β1（TGF-β1）和减少细胞外基质产生来实现的。在人肾小球系膜细胞中，高葡萄糖诱导 ROS 产生并激活 Nrf2 及其下游基因的表达。此外，Nrf2 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 siRNA 敲低 Nrf2 则增强 TGF-β1 的转录和纤连蛋白的产生。

结论

这项工作清楚地表明 Nrf2 在糖尿病肾病中具有保护作用，表明饮食或治疗性激活 Nrf2 可以用作预防或减缓糖尿病肾病进展的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/d69ffceb1f7e/zdb0041060830006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/a36de2d0252b/zdb0041060830001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/b681992dd3a3/zdb0041060830002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/f354af3acf6e/zdb0041060830003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/feb9e6cd551c/zdb0041060830005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/d69ffceb1f7e/zdb0041060830006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/a36de2d0252b/zdb0041060830001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/b681992dd3a3/zdb0041060830002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/f354af3acf6e/zdb0041060830003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/feb9e6cd551c/zdb0041060830005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ff/2844833/d69ffceb1f7e/zdb0041060830006.jpg

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