FKN Facilitates HK-2 Cell EMT and Tubulointerstitial Lesions via the Wnt/β-Catenin Pathway in a Murine Model of Lupus Nephritis
FKN Facilitates HK-2 Cell EMT and Tubulointerstitial Lesions via the Wnt/β-Catenin Pathway in a Murine Model of Lupus Nephritis
复制标题
FKN 在狼疮性肾炎小鼠模型中通过 Wnt/β-Catenin 通路促进 HK-2 细胞 EMT 和肾小管间质病变
DOI：
10.3389/fimmu.2019.00784
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发表时间：
2019-04-30
影响因子：
7.3
通讯作者：
You, Yanwu
中科院分区：
文献类型：
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作者：
Fu, Dongdong;Senouthai, Soulixay;You, Yanwu
Fractalkine（FKN），也称为趋化因子（C-X3-C基序）配体1，构成了一种有趣的趋化因子，其在包括自身免疫性疾病在内的许多炎性疾病的发展中具有记录的作用。具体而言，据报道，FKN参与狼疮性肾炎（LN）的疾病进展。上皮间质转化（EMT）在肾小管间质病变（TIL）的形成中起着重要作用，而TIL越来越被认为是损伤后组织纤维化的标志。然而，LN中FKN与EMT或TIL之间的相关性尚未确定。为了研究FKN在EMT和TIL中的潜在作用，用抗FKN抗体、重组FKN趋化因子结构域或同种型抗体处理MRL淋巴细胞增殖（MRL/Ipr）品系小鼠。我们的结果显示，用抗FKN抗体治疗改善了MRL/Ipr小鼠的EMT、TIL和肾功能，沿着抑制Wnt/β-连环蛋白信号通路的活化。相反，重组FKN趋化因子结构域的施用具有相反的效果。此外，为了进一步探索FKN在EMT中的作用，我们评估了FKN耗尽或过表达的人近端小管上皮HK-2细胞中EMT标志物的水平。我们的研究结果提供了第一个证据表明，E-cadherin水平上调，而α-SMA和波形蛋白的表达下调FKN耗尽HK-2细胞。相反，FKN在HK-2细胞中的过表达增强EMT。此外，XAV 939对WnT/β-连环蛋白通路的抑制抵消了FKN过表达的作用，而Ang II对WnT/β-连环蛋白通路的激活削弱了FKN敲除对HK-2细胞EMT的作用。总之，我们的数据表明，FKN在MRL/Ipr小鼠的EMT进展和TIL发展中起着重要作用，最有可能是通过激活Wnt/β-连环蛋白信号通路。
Fractalkine (FKN), also known as chemokine (C-X3-C motif) ligand 1, constitutes an intriguing chemokine with a documented role in the development of numerous inflammatory diseases including autoimmune disease. Specifically, it has been reported that FKN is involved in the disease progression of lupus nephritis (LN). The epithelial-mesenchymal transition (EMT) plays a significant role in the formation of tubulointerstitial lesions (TIL), which are increasingly recognized as a hallmark of tissue fibrogenesis after injury. However, the correlation between FKN and EMT or TIL in LN has not been determined. To investigate the potential role of FKN in EMT and TIL, MRL lymphoproliferation (MRL/Ipr) strain mice were treated with an anti-FKN antibody, recombinant-FKN chemokine domain, or isotype antibody. Our results revealed that treatment with the anti-FKN antibody improved EMT, TIL, and renal function in MRL/Ipr mice, along with inhibiting activation of the Wnt/beta-catenin signaling pathway. In contrast, administration of the recombinant-FKN chemokine domain had the opposite effect. Furthermore, to further explore the roles of FKN in EMT, we assessed the levels of EMT markers in FKN -depleted or overexpressing human proximal tubule epithelial HK-2 cells. Our results provide the first evidence that the E-cadherin level was upregulated, whereas alpha-SMA and vimentin expression was downregulated in FKN-depleted HK-2 cells. In contrast, overexpression of FKN in HK-2 cells enhanced EMT. In addition, inhibition of the WnT/beta-catenin pathway by XAV939 negated the effect of FKN overexpression, whereas activation of the WnT/beta-catenin pathway by Ang II impaired the effect of the FKN knockout on EMT in HK-2 cells. Together, our data indicate that FKN plays essential roles in the EMT progression and development of TIL in MRL/Ipr mice, most likely through activation of the Wnt/beta-catenin signaling pathway.