Nrf2 信号通路通过 PI3K/Akt 信号通路减弱上皮间质转化和肾间质纤维化。
Nrf2 signaling attenuates epithelial-to-mesenchymal transition and renal interstitial fibrosis via PI3K/Akt signaling pathways.
机构信息
Department of Urology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
Department of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
出版信息
Exp Mol Pathol. 2019 Dec;111:104296. doi: 10.1016/j.yexmp.2019.104296. Epub 2019 Aug 23.
BACKGROUND
Nrf2 constitutes a therapeutic reference point for renal fibrosis and chronic kidney diseases. Nrf2-related signaling pathways are recognized to temper endothelial-to-mesenchymal transition (EMT) in fibrotic tissue. Nevertheless, the mechanism by which Nrf2 mitigates renal interstitial fibrosis is imprecise.
METHODS
The relationship between Nrf2 and renal interstitial fibrosis was investigated using the unilateral ureteral obstruction (UUO) model of Nrf2 mice. The mice were separated into four groups, based on the treatment and intervention: Nrf2 + UUO, Nrf2 + Sham, WT + UUO and WT + Sham. Histological examination of renal tissue following the hematoxylin-eosin and Masson staining was carried out, as well as immunohistochemical staining. Additionally, to confirm the in vivo discoveries, in vitro experiments with HK-2 cells were also performed.
RESULTS
The Nrf2 + UUO group showed more severe renal interstitial fibrosis compared to the WT + UUO, Nrf2 + Sham and WT + Sham groups. Furthermore, the manifestations of α-SMA and Fibronectin significantly increased, and the manifestation of E-cadherin considerably decreased in kidney tissues from the group of Nrf2 + UUO, compared to the WT + UUO group. The Nrf2 protein level significantly decreased in HK-2 cells, in reaction to the TGF-β1 concentration. In addition, the overexpression of Nrf2 presented contradictory results. What is more, the PI3K/Akt signaling pathway was discovered to be activated in the proteins extracted from cultured cells, and treated with Nrf2 siRNA and kidney tissues from the Nrf2 + UUO group.
CONCLUSIONS
The results we obtained demonstrate that Nrf2 signaling pathway may perhaps offset the development of EMT, prompted by TGF-β1 and renal interstitial fibrosis. Likewise, the anti-fibrotic effect of Nrf2 was imparted by the inactivation of PI3K/Akt signaling. From our discoveries, we deliver new insight related to the prevention and treatment of kidney fibrosis.
背景
Nrf2 是肾脏纤维化和慢性肾脏病的治疗参考点。现已证实，Nrf2 相关信号通路可调节纤维化组织中的内皮-间质转化（EMT）。然而，Nrf2 减轻肾间质纤维化的机制尚不清楚。
方法
采用单侧输尿管梗阻（UUO）Nrf2 小鼠模型研究 Nrf2 与肾间质纤维化的关系。根据处理和干预措施，将小鼠分为四组：Nrf2+UUO、Nrf2+Sham、WT+UUO 和 WT+Sham。对肾组织进行苏木精-伊红和 Masson 染色及免疫组化染色的组织学检查，同时进行了体外 HK-2 细胞实验。
结果
与 WT+UUO、Nrf2+Sham 和 WT+Sham 组相比，Nrf2+UUO 组的肾间质纤维化更为严重。此外，与 WT+UUO 组相比，Nrf2+UUO 组肾组织中 α-SMA 和纤维连接蛋白的表达明显增加，E-钙黏蛋白的表达明显减少。与 TGF-β1 浓度相对应，HK-2 细胞中 Nrf2 蛋白水平显著降低。此外，Nrf2 的过表达呈现出相反的结果。此外，还发现 PI3K/Akt 信号通路在培养细胞提取的蛋白中被激活，并在 Nrf2 siRNA 处理和 Nrf2+UUO 组的肾组织中被激活。
结论
我们的研究结果表明，Nrf2 信号通路可能通过抑制 TGF-β1 诱导的 EMT 来抵消 EMT 的发展，从而减轻肾间质纤维化。此外，Nrf2 通过抑制 PI3K/Akt 信号通路发挥抗纤维化作用。我们的研究结果为肾脏纤维化的防治提供了新的见解。
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