Nrf2调控Wnt/β-catenin信号通路在急性肾损伤慢性化转归中的作用及机制

Oxidative stress is the initial step of the development of chronic kidney disease (CKD) from acute kidney injury (AKI). Nrf2 is the key target in regulating oxidative stress. Previous studies have demonstrated that Wnt/β-catenin signaling pathway plays an important role in the evolution of CKD from AKI, and Wnt/β-catenin signaling pathway can be activated by oxidative stress. In our previous study, we showed that impaired activation of Nrf2 was associated with aristolochic acid (AA)-induced AKI, and kidney injury could be ameliorated by activating Nrf2. However, the relationship between Nrf2 and Wnt/β-catenin signaling pathway and their role in the evolution of CKD from AKI remain unclear. The objectives of this study are to investigate the regulatory role of Nrf2 in Wnt/β-catenin signaling pathway, and its effect on the progression of AKI to CKD in AA-induced AKI model in vivo and in vitro. Nrf2 will be regulated by sulforaphane (upregulation) and Nrf2 gene knockout (downregulation) in this project. This study will likely reveal the relationship between Nrf2 and Wnt/β-catenin signaling pathway, which will provide experimental evidence for AKI to CKD progression mechanism and novel targets for its intervention.

氧化应激是急性肾损伤（AKI）向慢性肾脏病（CKD）进展的始动环节，Nrf2是调控氧化应激的关键靶点。研究表明Wnt/β-catenin信号通路在AKI向CKD转化中起重要作用，氧化应激可激活Wnt/β-catenin信号通路。我们以往研究报道，在马兜铃酸（AA）诱导的AKI中，肾小管上皮细胞Nrf2表达降低且活化受损，活化Nrf2可减轻AA引起的AKI。但Nrf2与Wnt/β-catenin信号通路的关系及其在AKI慢性转归中的作用尚不清楚。本项目以AA为损伤因子建立AKI小鼠和细胞模型，通过莱菔硫烷（SFN）活化Nrf2及特异性敲除Nrf2，明确Nrf2对Wnt/β-catenin信号通路的调控作用及对AKI慢性化转归的影响。本研究有助于揭示Nrf2与Wnt/β-catenin信号通路的关系，为AKI向CKD进展机制的阐明提供实验依据及干预靶点。

我们以往研究报道Nrf2在马兜铃酸(AA)诱导的急性肾损伤(AKI)中起重要作用。研究表明Wnt/β-catenin信号通路在AKI向慢性肾脏病(CKD)转化过程中具重要作用。但Nrf2与Wnt/β-catenin信号通路的关系及其在AKI慢性化转归中的作用尚不清楚。我们的研究结果发现：AA诱导的小鼠AKI慢性化阶段，Nrf2信号持续受损，Wnt/β-catenin信号通路活化，肾脏纤维化明显。Nrf2基因敲除使AA诱导的小鼠肾脏Wnt/β-catenin信号通路活化增强，肾脏纤维化进一步加重。β-catenin抑制剂能减轻AA诱导的Nrf2基因敲除小鼠AKI慢性化转归，减轻肾脏纤维化。体外研究显示上调AA刺激的NRK-52E细胞Nrf2表达可使其上清液培养的NRK-49F细胞纤维化减少，而下调AA刺激的NRK-52E细胞Nrf2表达可使其上清液培养的NRK-49F细胞纤维化增多，β-catenin抑制剂可减轻NRK-49F细胞纤维化。综上所述，本研究揭示了Nrf2活化受损调控Wnt/β-catenin信号通路活化在AA诱导的AKI慢性化转归中的关键作用，提示Nrf2/Wnt/β-catenin通路可以作为抑制AA诱导的AKI后慢性化转归的潜在治疗靶点，为预防和治疗AA诱导的AKI慢性化转归提供了新的思路。