MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Kidney Int. 2013 Dec;84(6):1090-5. doi: 10.1038/ki.2013.248. Epub 2013 Jun 19.
Multifaceted cell defense pathways perform a critical role in the maintenance of homeostasis at the cellular, tissue, and organism levels. The Keap1-Nrf2 pathway is one of the most important of these cytoprotective pathways, with Nrf2 serving as a master transcriptional regulator of the basal and inducible expression of a multitude of genes encoding detoxification enzymes, antioxidant proteins, xenobiotic transporters, and other stress-response mediators. An increasing body of evidence supports a vital physiological role for Nrf2 in protection of the kidney against a number of diseases, and the pharmacological induction of Nrf2 by bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate, CDDO-Me) has shown promise for the management of such pathologies. Acute kidney injury, induced by drugs and other stimuli, is a significant clinical problem, and accounts for the cessation of development of many promising drug candidates. A better understanding of the molecular mechanisms that underlie acute kidney injury, and the biological facets that determine the balance between renal adaptation and dysfunction, is therefore vital to reducing clinical burden and patient suffering. The focus of this review is to highlight recent work that has demonstrated an ability of Nrf2 to determine the sensitivity of the kidney to acute injury invoked by environmental insults such as heavy metals and ischemia, as well as xenobiotics such as cyclosporin A and cisplatin.
多方面的细胞防御途径在细胞、组织和器官水平上维持内环境稳态方面起着关键作用。Keap1-Nrf2 途径是这些细胞保护途径中最重要的途径之一，Nrf2 作为许多解毒酶、抗氧化蛋白、外源性化合物转运蛋白和其他应激反应介质的基础和诱导表达的主要转录调节因子。越来越多的证据支持 Nrf2 在保护肾脏免受多种疾病方面具有重要的生理作用，并且 bardoxolone 甲酯（甲基-2-氰基 3,12-二氧代辛烷-1,9-二烯-28-酸酯，CDDO-Me）通过药理学诱导 Nrf2 已显示出用于管理此类病理的潜力。由药物和其他刺激物引起的急性肾损伤是一个重大的临床问题，导致许多有前途的药物候选物的开发停止。因此，更好地了解急性肾损伤的分子机制以及决定肾脏适应和功能障碍之间平衡的生物学方面，对于减轻临床负担和患者痛苦至关重要。本综述的重点是强调最近的工作，这些工作表明 Nrf2 能够确定肾脏对环境刺激（如重金属和缺血）以及环孢素 A 和顺铂等外源性化合物引起的急性损伤的敏感性。
