Activation of podocyte Notch mediates early Wt1 glomerulopathy.
Activation of podocyte Notch mediates early Wt1 glomerulopathy.
复制标题
DOI：
10.1016/j.kint.2017.11.014
复制
发表时间：
2018-04
影响因子：
19.6
通讯作者：
Waters AM
中科院分区：
文献类型：
--
作者：
Asfahani RI;Tahoun MM;Miller-Hodges EV;Bellerby J;Virasami AK;Sampson RD;Moulding D;Sebire NJ;Hohenstein P;Scambler PJ;Waters AM
Wilms 肿瘤抑制基因 WT1 编码调节足细胞发育的锌指蛋白，并在成熟足细胞中高度表达。 WT1基因突变与肾小球内疤痕组织形成导致的肾衰竭的发生有关，但其机制尚不清楚。在这里，我们使用基于他莫昔芬的 CRE-LoxP 系统诱导成年小鼠 Wt1 缺失，以研究肾小球硬化进化的机制。足细胞凋亡早在诱导后第四天就很明显，并且在疾病进展过程中增加，这支持了 Wt1 在成熟足细胞存活中的作用。疾病发作时足细胞 Notch 激活明显，Notch1 及其转录靶标（包括 Nrarp）上调。足细胞 FoxC2 受到抑制，Hey2 上调，支持 Wt1/FoxC2/Notch 转录网络在成熟足细胞损伤中的作用。突变小鼠足细胞中剪切的Notch1和HES1蛋白的表达在疾病早期得到证实。此外，足细胞 HES1 表达的诱导与上皮间质转化相关基因的上调相关，从而表明 HES1 介导足细胞 EMT。最后，Notch 信号传导的早期药理抑制可改善肾小球疤痕和蛋白尿。因此，成熟足细胞中 Wt1 的缺失可调节足细胞 Notch 激活，从而介导 WT1 相关肾小球硬化的早期事件。
The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.
登录
查看更多内容
影响因子：
3.7
作者：
Morimoto M;Myung C;Beirnes K;Choi K;Asakura Y;Bokenkamp A;Bonneau D;Brugnara M;Charrow J;Colin E;Davis A;Deschenes G;Gentile M;Giordano M;Gormley AK;Govender R;Joseph M;Keller K;Lerut E;Levtchenko E;Massella L;Mayfield C;Najafian B;Parham D;Spranger J;Stenzel P;Yis U;Yu Z;Zonana J;Hendson G;Boerkoel CF
通讯作者：
Boerkoel CF
影响因子：
8.3
作者：
JOHNS, DW;CAREY, RM;PEACH, MJ
通讯作者：
PEACH, MJ
影响因子：
30.8
作者：
BRUENING, W;BARDEESY, N;PELLETIER, J
通讯作者：
PELLETIER, J
解密边缘介导的凹口代码：识别激活和抑制位点，允许歧视配体之间。
影响因子：
11.8
作者：
Kakuda S;Haltiwanger RS
通讯作者：
Haltiwanger RS
成年小鼠肝细胞和B淋巴细胞向神经干细胞的直接谱系转化。
影响因子：
5.9
作者：
Cassady JP;D'Alessio AC;Sarkar S;Dani VS;Fan ZP;Ganz K;Roessler R;Sur M;Young RA;Jaenisch R
通讯作者：
Jaenisch R