Podocyte-Specific Deletion of Murine CXADR Does Not Impair Podocyte Development, Function or Stress Response

The coxsackie- and adenovirus receptor (CXADR) is a member of the immunoglobulin protein superfamily, present in various epithelial cells including glomerular epithelial cells. Beside its known function as a virus receptor, it also constitutes an integral part of cell-junctions. Previous studies in the zebrafish pronephros postulated a potential role of CXADR for the terminal differentiation of glomerular podocytes and correct patterning of the elaborated foot process architecture. However, due to early embryonic lethality of constitutive Cxadr knockout mice, mammalian data on kidney epithelial cells have been lacking. Interestingly, Cxadr is robustly expressed during podocyte development and in adulthood in response to glomerular injury. We therefore used a conditional transgenic approach to elucidate the function of Cxadr for podocyte development and stress response. Surprisingly, we could not discern a developmental phenotype in podocyte specific Cxadr knock-out mice. In addition, despite a significant up regulation of CXADR during toxic, genetic and immunologic podocyte injury, we could not detect any impact of Cxadr on these injury models. Thus these data indicate that in contrast to lower vertebrate models, mammalian podocytes have acquired molecular programs to compensate for the loss of Cxadr.

柯萨奇病毒与腺病毒受体（coxsackie- and adenovirus receptor, CXADR）属于免疫球蛋白蛋白超家族成员，广泛表达于包括肾小球上皮细胞在内的多种上皮细胞中。除作为病毒受体的已知功能外，它亦是细胞连接的核心组成部分。既往基于斑马鱼原肾的研究推测，CXADR可能参与肾小球足细胞的终末分化，并对复杂足突结构的正确构建发挥调控作用。然而，由于全身敲除Cxadr基因的小鼠会出现早期胚胎致死，因此目前尚缺乏肾脏上皮细胞相关的哺乳动物实验数据。值得注意的是，在足细胞发育阶段及成年机体发生肾小球损伤时，Cxadr的表达会显著上调。为此，我们采用条件性转基因技术，以阐明Cxadr在足细胞发育及应激反应中的功能。令人意外的是，在足细胞特异性敲除Cxadr的小鼠中，我们未观察到明显的发育表型。此外，尽管在毒性损伤、遗传损伤及免疫性足细胞损伤模型中，CXADR的表达均出现显著上调，但我们并未发现Cxadr对这类损伤模型存在任何影响。综上，本研究数据表明，与低等脊椎动物模型不同，哺乳动物足细胞已演化出可代偿Cxadr缺失的分子调控程序。