Ectopic notch activation in developing podocytes causes glomerulosclerosis.
Ectopic notch activation in developing podocytes causes glomerulosclerosis.
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DOI：
10.1681/asn.2007050596
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发表时间：
2008-06
期刊：
影响因子：
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通讯作者：
A. Waters;M. Wu;T. Onay;Jacob Scutaru;Ju Liu;C. Lobe;S. Quaggin;T. Piscione
中科院分区：
文献类型：
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作者：
A. Waters;M. Wu;T. Onay;Jacob Scutaru;Ju Liu;C. Lobe;S. Quaggin;T. Piscione
遗传证据支持 Notch 信号在肾小球发育过程中足细胞命运中的早期作用。确定细胞命运后，发育中的足细胞中 Notch 转录靶标的表达减少，表明组成型 Notch 信号传导可能会阻碍足细胞分化。本研究通过在转基因小鼠发育中的足细胞中异位表达 Notch 胞内结构域 (NOTCH-IC)（Notch 受体蛋白水解裂解的生物活性细胞内产物）来确定组成型 Notch 信号传导对足细胞分化的影响。组织学和分子分析显示新生 NOTCH-IC 表达小鼠肾小球形态正常，足细胞标记物表达正常；然而，小鼠在出生后 2 周出现严重蛋白尿并显示出进行性肾小球硬化的证据。成熟足细胞的特征丧失：足突消失； Wt1、Nphs1、Nphs2表达下调；诱导细胞周期重入； Pax2的表达增加。相比之下，足细胞特异性 Rbpsuh 失活的小鼠似乎正常，Rbpsuh 编码一种对规范 Notch 信号传导至关重要的蛋白质。此外，在小鼠足细胞中同时条件性灭活 Rbpsuh 后，转基因小鼠中 NOTCH-IC 表达的破坏作用得到了预防。这些结果表明，Notch 信号传导在足细胞终末分化过程中是可有可无的，但组成型（或不适当的）Notch 信号传导是有害的，会导致肾小球硬化。
Genetic evidence supports an early role for Notch signaling in the fate of podocytes during glomerular development. Decreased expression of Notch transcriptional targets in developing podocytes after the determination of cell fate suggests that constitutive Notch signaling may oppose podocyte differentiation. This study determined the effects of constitutive Notch signaling on podocyte differentiation by ectopically expressing Notch's intracellular domain (NOTCH-IC), the biologically active, intracellular product of proteolytic cleavage of the Notch receptor, in developing podocytes of transgenic mice. Histologic and molecular analyses revealed normal glomerular morphology and expression of podocyte markers in newborn NOTCH-IC-expressing mice; however, mice developed severe proteinuria and showed evidence of progressive glomerulosclerosis at 2 wk after birth. Features of mature podocytes were lost: Foot processes were effaced; expression of Wt1, Nphs1, and Nphs2 was downregulated; cell-cycle re-entry was induced; and the expression of Pax2 was increased. In contrast, mice with podocyte-specific inactivation of Rbpsuh, which encodes a protein essential for canonical Notch signaling, seemed normal. In addition, the damaging effects of NOTCH-IC expression were prevented in transgenic mice after simultaneous conditional inactivation of Rbpsuh in murine podocytes. These results suggest that Notch signaling is dispensable during terminal differentiation of podocytes but that constitutive (or inappropriate) Notch signaling is deleterious, leading to glomerulosclerosis.