The transcription factor Dach1 is essential for podocyte function.
The transcription factor Dach1 is essential for podocyte function.
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DOI：
10.1111/jcmm.13544
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发表时间：
2018-05
影响因子：
5.3
通讯作者：
Endlich K
中科院分区：
文献类型：
--
作者：
Endlich N;Kliewe F;Kindt F;Schmidt K;Kotb AM;Artelt N;Lindenmeyer MT;Cohen CD;Döring F;Kuss AW;Amann K;Moeller MJ;Kabgani N;Blumenthal A;Endlich K
足细胞去分化和丢失是慢性肾脏疾病的主要原因。在全基因组相关性研究中发现，Dach1是一种对细胞命运至关重要的转录因子，与肾小球滤过率有关。我们发现足细胞在体内表达高水平的Dach1，在体外表达低得多的Dach1。壁上皮细胞(PECs)是足细胞的一种祖细胞，目前仍在争论中，Dach1的表达水平很低。免疫细胞化学和Western印迹显示，将编码Dach1基因的质粒导入PECs后，可诱导足细胞特异性蛋白突触素的表达。此外，在Dach1表达的PECs中，突触素沿肌动蛋白纤维呈点状分布，与分化的足细胞相似。此外，去分化的肾小球足细胞在细胞培养9天后，Dach1和突触素的表达显著减少。为了研究Dach1在体内的作用，我们以斑马鱼幼体为动物模型。通过在受精卵中注射吗啡将斑马鱼同源基因Dachd击倒，导致了严重的肾脏表型。斑马鱼仔鱼肾小球的形态发生改变，并伴有肾小球蛋白的下调和滤过屏障的渗漏。有趣的是，与对照组相比，糖尿病肾病患者的肾小球活检组织中Dach1和突触素的表达也显著减少。综上所述，Dach1是一种转录因子，对足细胞分化和正常的肾脏功能至关重要。
Dedifferentiation and loss of podocytes are the major cause of chronic kidney disease. Dach1, a transcription factor that is essential for cell fate, was found in genome‐wide association studies to be associated with the glomerular filtration rate. We found that podocytes express high levels of Dach1 in vivo and to a much lower extent in vitro. Parietal epithelial cells (PECs) that are still under debate to be a type of progenitor cell for podocytes expressed Dach1 only at low levels. The transfection of PECs with a plasmid encoding for Dach1 induced the expression of synaptopodin, a podocyte‐specific protein, demonstrated by immunocytochemistry and Western blot. Furthermore, synaptopodin was located along actin fibres in a punctate pattern in Dach1‐expressing PECs comparable with differentiated podocytes. Moreover, dedifferentiating podocytes of isolated glomeruli showed a significant reduction in the expression of Dach1 together with synaptopodin after 9 days in cell culture. To study the role of Dach1 in vivo, we used the zebrafish larva as an animal model. Knockdown of the zebrafish ortholog Dachd by morpholino injection into fertilized eggs resulted in a severe renal phenotype. The glomeruli of the zebrafish larvae showed morphological changes of the glomerulus accompanied by down‐regulation of nephrin and leakage of the filtration barrier. Interestingly, glomeruli of biopsies from patients suffering from diabetic nephropathy showed also a significant reduction of Dach1 and synaptopodin in contrast to control biopsies. Taken together, Dach1 is a transcription factor that is important for podocyte differentiation and proper kidney function.
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5.3
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