The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice.
The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice.
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NRF2三萜活化剂CDDO-咪唑啉剂可保护肾脏免受小鼠缺血 - 再灌注损伤。
DOI：
10.1038/ki.2013.357
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发表时间：
2014-01
影响因子：
19.6
通讯作者：
Rabb H
中科院分区：
文献类型：
--
作者：
Liu M;Reddy NM;Higbee EM;Potteti HR;Noel S;Racusen L;Kensler TW;Sporn MB;Reddy SP;Rabb H
缺血再灌注引起的急性肾损伤（阿基）是自体肾和移植肾的主要临床问题。我们先前表明，Nrf 2（一种与抗氧化反应元件结合的有效bZIP转录因子）的缺乏增强了对实验性缺血性阿基的易感性。在这里，我们通过用合成的三萜类化合物CDDO-咪唑啉在体内和体外扩增Nrf 2活化来进一步探索Nrf 2在阿基中的作用。用CDDO-咪唑啉治疗并经历实验性双侧缺血性阿基的小鼠的存活率和肾功能得到改善。与溶剂处理的小鼠相比，处理的小鼠具有改善的肾组织学，肾小管损伤减少，以及促炎细胞因子和趋化因子产生减少。在保护机制的探索中，我们发现在CDDO-咪唑啉处理的小鼠肾脏中Nrf 2靶抗氧化基因的上调。此外，用CDDO-咪唑啉治疗的Nrf 2缺陷小鼠在死亡率、肾功能或组织学、促炎细胞因子基因表达方面没有显著改善，并且抗氧化剂基因表达没有显著增加。体外研究表明，肾上皮细胞可能是CDDO-咪唑啉的重要靶点。因此，用CDDO-咪唑啉激活Nrf 2信号传导可保护阿基，并为这种常见和严重的疾病提供了新的治疗机会。
Acute kidney injury (AKI) caused by ischemia reperfusion is a major clinical problem in both native and transplanted kidneys. We previously showed that deficiency of Nrf2, a potent bZIP transcription factor that binds to the antioxidant response element, enhances susceptibility to experimental ischemic AKI. Here we further explored the role of Nrf2 in AKI by amplifying Nrf2 activation in vivo and in vitro with the synthetic triterpenoid CDDO-imidazolide. Mice treated with CDDO-imidazolide and undergoing experimental bilateral ischemic AKI had improved survival and renal function. Treated mice had improved renal histology with a decrease in tubular injury, as well as a decrease in pro-inflammatory cytokine and chemokine production compared to vehicle-treated mice. In an exploration of protective mechanisms, we found an up-regulation of Nrf2 target antioxidant genes in CDDO-imidazolide treated mouse kidneys. Furthermore, Nrf2 deficient mice treated with CDDO-imidazolide had no significant improvement in mortality, renal function or histology, pro-inflammatory cytokine gene expression, and no significant increase in antioxidant gene expression. In vitro studies demonstrated that the renal epithelial cells were likely an important target of CDDO-imidazolide. Thus, activation of Nrf2 signaling with CDDO-imidazolide confers protection from AKI, and presents a new therapeutic opportunity for this common and serious condition.