Loss of MEN1 leads to renal fibrosis and decreases HGF-Adamts5 pathway activity via an epigenetic mechanism.
Loss of MEN1 leads to renal fibrosis and decreases HGF-Adamts5 pathway activity via an epigenetic mechanism.
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MEN1的丧失会导致肾纤维化，并通过表观遗传机制降低HGF-ADAMTS5途径活性。
DOI：
10.1002/ctm2.982
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发表时间：
2022-08
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
肾纤维化是导致慢性肾脏疾病发展的严重病症。MEN 1基因是编码menin蛋白的表观遗传调节因子，其在肾组织中的作用尚不清楚。在苏木精-伊红染色的石蜡切片上检查肾脏组织学。Masson三色染色和天狼星红染色分析肾纤维化。分别通过定量真实的时间PCR（qPCR）和蛋白质印迹法测定基因和蛋白质表达。使用小鼠或患者肾组织中的免疫组织化学染色来评估蛋白质水平。流式细胞仪检测细胞周期分布及凋亡情况。对Men 1f/f和Men 1f/f小鼠肾组织中的差异表达基因进行RNA测序。进行染色质免疫沉淀测序（ChIP‐seq）以鉴定小鼠肾组织中全基因组内的menin和H3 K4 me 3富集区域。对menin和H3 K4 me 3在基因启动子区的占有率进行ChIP-qPCR测定。荧光素酶报告基因检测启动子活性。使用Men 1f/f和Men 1xl/xl小鼠的单侧输尿管梗阻（UUO）加重模型评估rh-HGF对肾纤维化的药理学作用。MEN 1的表达在纤维化小鼠和人类糖尿病患者的肾组织中减少，并且用纤维化因子治疗导致肾小管上皮细胞（RTEC）中MEN 1表达的下调。RTEC中MEN 1的破坏导致α-SMA和胶原蛋白1的高表达，而MEN 1过表达抑制TGF-β处理诱导的上皮向间质转化（EMT）。MEN 1的条件性敲除导致慢性肾纤维化和UUO诱导的肾小管间质纤维化（TIF），其与EMT、G2/M停滞和JNK信号传导的诱导增加相关。从机制上讲，menin招募并增加肝细胞生长因子（HGF）和具有血小板反应蛋白基序5（Adamts 5）基因的去整合素和金属蛋白酶启动子区的H3 K4 me 3，并增强其转录激活。在UUO小鼠模型中，外源性HGF恢复了Adamts 5的表达，并改善了Men 1缺乏诱导的肾纤维化。这些发现表明，MEN 1是肾纤维化发生中的重要抗纤维化因子，并可能成为抗纤维化治疗的潜在靶点。 MEN 1缺乏导致慢性肾纤维化MEN 1缺乏触发EMT、G2/M期阻滞和JNK信号转导激活Hgf‐ Adamts 5是一个受menin表观遗传学调控的新靶基因
Renal fibrosis is a serious condition that results in the development of chronic kidney diseases. The MEN1 gene is an epigenetic regulator that encodes the menin protein and its role in kidney tissue remains unclear. Kidney histology was examined on paraffin sections stained with hematoxylin‐eosin staining. Masson’s trichrome staining and Sirius red staining were used to analyze renal fibrosis. Gene and protein expression were determined by quantitative real‐time PCR (qPCR) and Western blot, respectively. Immunohistochemistry staining in the kidney tissues from mice or patients was used to evaluate protein levels. Flow cytometry was used to analyze the cell cycle distributions and apoptosis. RNA‐sequencing was performed for differential expression genes in the kidney tissues of the Men1f/f and Men1∆/∆ mice. Chromatin immunoprecipitation sequencing (ChIP‐seq) was carried out for identification of menin‐ and H3K4me3‐enriched regions within the whole genome in the mouse kidney tissue. ChIP‐qPCR assays were performed for occupancy of menin and H3K4me3 at the gene promoter regions. Luciferase reporter assay was used to detect the promoter activity. The exacerbated unilateral ureteral obstruction (UUO) models in the Men1f/f and Men1∆/∆ mice were used to assess the pharmacological effects of rh‐HGF on renal fibrosis. The expression of MEN1 is reduce in kidney tissues of fibrotic mouse and human diabetic patients and treatment with fibrotic factor results in the downregulation of MEN1 expression in renal tubular epithelial cells (RTECs). Disruption of MEN1 in RTECs leads to high expression of α‐SMA and Collagen 1, whereas MEN1 overexpression restrains epithelial‐to‐mesenchymal transition (EMT) induced by TGF‐β treatment. Conditional knockout of MEN1 resulted in chronic renal fibrosis and UUO‐induced tubulointerstitial fibrosis (TIF), which is associated with an increased induction of EMT, G2/M arrest and JNK signaling. Mechanistically, menin recruits and increases H3K4me3 at the promoter regions of hepatocyte growth factor (HGF) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (Adamts5) genes and enhances their transcriptional activation. In the UUO mice model, exogenous HGF restored the expression of Adamts5 and ameliorated renal fibrosis induced by Men1 deficiency. These findings demonstrate that MEN1 is an essential antifibrotic factor in renal fibrogenesis and could be a potential target for antifibrotic therapy. MEN1 deficiency leads to chronic renal fibrosis MEN1 deficiency triggers EMT, G2/M arrest and JNK signaling activation Hgf‐Adamts5 is a novel target gene that is epigenetically regulated by menin
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影响因子：
16.6
作者：
Fernandez-Cuesta, Lynnette;Peifer, Martin;Lu, Xin;Sun, Ruping;Ozretic, Luka;Seidel, Danila;Zander, Thomas;Leenders, Frauke;George, Julie;Mueller, Christian;Dahmen, Ilona;Pinther, Berit;Bosco, Graziella;Konrad, Kathryn;Altmueller, Janine;Nuernberg, Peter;Achter, Viktor;Lang, Ulrich;Schneider, Peter M.;Bogus, Magdalena;Soltermann, Alex;Brustugun, Odd Terje;Helland, Aslaug;Solberg, Steinar;Lund-Iversen, Marius;Ansen, Sascha;Stoelben, Erich;Wright, Gavin M.;Russell, Prudence;Wainer, Zoe;Solomon, Benjamin;Field, John K.;Hyde, Russell;Davies, Michael P. A.;Heukamp, Lukas C.;Petersen, Iver;Perner, Sven;Lovly, Christine M.;Cappuzzo, Federico;Travis, William D.;Wolf, Juergen;Vingron, Martin;Brambilla, Elisabeth;Haas, Stefan A.;Buettner, Reinhard;Thomas, Roman K.
通讯作者：
Thomas, Roman K.
影响因子：
8.8
作者：
Dreijerink KMA;Groner AC;Vos ESM;Font-Tello A;Gu L;Chi D;Reyes J;Cook J;Lim E;Lin CY;de Laat W;Rao PK;Long HW;Brown M
通讯作者：
Brown M
DOI：
10.1161/atvbaha.117.310562
发表时间：
2018-07
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Fava M;Barallobre-Barreiro J;Mayr U;Lu R;Didangelos A;Baig F;Lynch M;Catibog N;Joshi A;Barwari T;Yin X;Jahangiri M;Mayr M
通讯作者：
Mayr M
影响因子：
0.9
作者：
Franquesa, M.;Riera, M.;Grinyo, J. M.
通讯作者：
Grinyo, J. M.
影响因子：
64.8
作者：
Huang, Jing;Gurung, Buddha;Wan, Bingbing;Matkar, Smita;Veniaminova, Natalia A.;Wan, Ke;Merchant, Juanita L.;Hua, Xianxin;Lei, Ming
通讯作者：
Lei, Ming