The podocyte protein nephrin is required for cardiac vessel formation
The podocyte protein nephrin is required for cardiac vessel formation
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DOI：
10.1093/hmg/ddr106
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Wagner, Kay-Dietrich
中科院分区：
文献类型：
--
作者：
Wagner, Nicole;Morrison, Harris;Wagner, Kay-Dietrich
Nephrin （NPHS1）是一种重要的肾足细胞结构蛋白。这种基因的突变导致芬兰型先天性肾病综合征。最近，肾素作为一种信号分子在肾足细胞中的作用已被确定。在这里，我们发现肾素不仅在肾足细胞中起作用，而且在心血管发育中也是必需的。在人和小鼠的胚胎发育过程中，肾素在心外膜和冠状血管中表达。Nephrin敲除胚胎显示心外膜细胞形态异常，在发育后期，由于细胞凋亡增加，冠状血管数量减少，此外，心脏纤维化。冠状血管形成所必需的连接蛋白43在肾素敲除胚胎中下调。p75NTR神经营养因子受体，一种已知的细胞凋亡介质，在突变体中表达增加。此外，共免疫沉淀研究表明，nephrin与p75NTR直接相互作用。原代肾素缺乏心肌细胞对神经生长因子祖细胞的凋亡率比野生型细胞高5倍，可通过RNAi对p75NTR进行拯救。综上所述，我们的数据表明，nephrin直接与p75NTR相互作用，并通过允许心血管祖细胞存活，揭示了nephrin在小鼠心脏发育中的重要作用。
Nephrin (NPHS1) has been described as an important structural protein of kidney podocytes. Mutations in this gene lead to the Finnish-type congenital nephrotic syndrome. More recently, a role of nephrin as a signalling molecule in kidney podocytes has been identified. Here, we show that nephrin not only has a function in kidney podocytes, but is also required for cardiovascular development. Nephrin is expressed in the epicardium and coronary vessels during human and mouse embryonic development. Nephrin knockout embryos showed abnormal epicardial cell morphology and, at later stages of development, a reduced number of coronary vessels due to increased apoptosis, and in addition, cardiac fibrosis. Connexin 43, which is required for coronary vessel formation, was downregulated in nephrin knockout embryos. Expression of the p75NTR neurotrophin receptor, a known mediator of apoptosis, was increased in mutants. Furthermore, co-immunoprecipitation studies demonstrated a direct interaction of nephrin with p75NTR. Primary nephrin-deficient cardiac cells showed a 5-fold higher rate of apoptosis in response to progenitor of nerve growth factor compared with wild-type cells, which could be rescued by RNAi against p75NTR. Taken together, our data demonstrate that nephrin directly interacts with p75NTR and reveal an important role for nephrin in murine cardiac development by permitting survival of cardiovascular progenitor cells.