FoxM1 promotes Wnt/β-catenin pathway activation and renal fibrosis via transcriptionally regulating multi-Wnts expressions.
FoxM1 promotes Wnt/β-catenin pathway activation and renal fibrosis via transcriptionally regulating multi-Wnts expressions.
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FoxM1通过转录调节多Wnts表达促进Wnt/β-catenin通路激活和肾纤维化
DOI：
10.1111/jcmm.15948
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发表时间：
2021-03
影响因子：
5.3
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Xie H;Miao N;Xu D;Zhou Z;Ni J;Yin F;Wang Y;Cheng Q;Chen P;Li J;Zheng P;Zhou L;Liu J;Zhang W;Wang X;Lu L
Wnt/β-catenin通路的激活在促进肾纤维化中起关键作用。Wnt/β-catenin通路的激活依赖于Wnt与细胞膜上Frizzled受体的结合。然而，调节Wnts生产的因素仍不清楚。在这里，我们证明了转录因子FoxM 1在梗阻性肾脏和纤维化患者的肾脏中显著增加。FoxM 1表达上调主要分布于肾小管上皮细胞。FoxM 1的药理学抑制下调UUO小鼠中的多Wnt升高并减弱肾纤维化。在培养的肾小管上皮细胞中，FoxM 1的过表达促进了8种Wnt的表达，而FoxM 1的敲低抑制了Ang II诱导的包括Wnt 1、Wnt 2b和Wnt 3在内的多种Wnt的表达。染色质免疫沉淀PCR证实FoxM 1与Wnt 1、Wnt 2b、Wnt 3启动子结合，荧光素酶检测进一步证实Wnt 1、Wnt 2b、Wnt 3转录受FoxM 1调控。因此，我们的研究结果表明，多Wnt家族成员受到转录因子FoxM 1的调控。FoxM 1可能是激活β-catenin通路和肾纤维化的关键开关。因此，FoxM 1可能是控制肾纤维化的潜在治疗靶点。
The activation of Wnt/β‐catenin pathway plays a pivotal role in promoting renal fibrosis. The activation of Wnt/β‐catenin pathway relies on the binding of Wnts to Frizzled receptors on cell membrane. However, the factor regulating Wnts production remains unclear. Here, we demonstrated that transcriptional factor FoxM1 was significantly increased in obstructed kidneys and patients' kidneys with fibrosis. The up‐regulation of FoxM1 mainly distributed in tubular epithelial cells. Pharmacological inhibition of FoxM1 down‐regulated multi‐Wnts elevation in UUO mice and attenuated renal fibrosis. In cultured renal tubular epithelial cells, overexpression of FoxM1 promoted 8 Wnts expression, while knock‐down on FoxM1‐suppressed multi‐Wnts including Wnt1, Wnt2b and Wnt3 expression induced by Ang II. Chromatin immunoprecipitation PCR confirmed that FoxM1 bound to Wnt1, Wnt2b, Wnt3 promoters and luciferase assay further identified that the transcriptions of Wnt1, Wnt2b and Wnt3 were regulated by FoxM1. Thus, our findings show that multi‐Wnt family members were regulated by transcriptional factor FoxM1. FoxM1 might be a key switch for activating β‐catenin pathway and renal fibrosis. Therefore, FoxM1 might be a potential therapeutic target in manipulating renal fibrosis.
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DOI：
10.1084/jem.20091857
发表时间：
2010-08-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Mirza MK;Sun Y;Zhao YD;Potula HH;Frey RS;Vogel SM;Malik AB;Zhao YY
通讯作者：
Zhao YY
影响因子：
50.3
作者：
Zhang N;Wei P;Gong A;Chiu WT;Lee HT;Colman H;Huang H;Xue J;Liu M;Wang Y;Sawaya R;Xie K;Yung WK;Medema RH;He X;Huang S
通讯作者：
Huang S
影响因子：
21.3
作者：
Laoukili, J;Kooistra, MRH;Medema, RH
通讯作者：
Medema, RH
影响因子：
9.2
作者：
Korver, W;Schilham, MW;Clevers, H
通讯作者：
Clevers, H
影响因子：
13.6
作者：
Maarouf, Omar H.;Aravamudhan, Anusha;Hunnphreys, Benjamin D.
通讯作者：
Hunnphreys, Benjamin D.