The Notch pathway in podocytes plays a role in the development of glomerular disease
The Notch pathway in podocytes plays a role in the development of glomerular disease
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DOI：
10.1038/nm1731
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发表时间：
2008-03-01
期刊：
影响因子：
82.9
通讯作者：
Susztak, Katalin
中科院分区：
文献类型：
--
作者：
Niranjan, Thiruvur;Bielesz, Bernhard;Susztak, Katalin
与肾小球硬化相关的蛋白尿导致肾功能进行性下降，影响数百万人。在这里，我们报告的Notch途径，这是至关重要的肾小球图案的激活，有助于肾小球疾病的发展。在糖尿病肾病和局灶节段性肾小球硬化的肾小球上皮细胞中，Notch 1（ICN 1）的细胞内结构域表达增加。ICN 1在足细胞中的条件性再表达导致蛋白尿和肾小球硬化。体外和体内研究表明，ICN 1通过激活p53诱导足细胞凋亡。特异性地在足细胞中的Notch转录伴侣（Rbpj）的遗传缺失或Notch途径的药理学抑制（用γ-分泌酶抑制剂）保护患有蛋白尿肾病的大鼠。总的来说，我们的观察表明，成熟足细胞中的Notch激活是肾小球疾病发病机制中的一种新机制，因此可能代表一种新的治疗靶点。
Albuminuria associated with sclerosis of the glomerulus leads to a progressive decline in renal function affecting millions of people. Here we report that activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease. Expression of the intracellular domain of Notch1 (ICN1) was increased in glomerular epithelial cells in diabetic nephropathy and in focal segmental glomerulosclerosis. Conditional re-expression of ICN1 in vivo exclusively in podocytes caused proteinuria and glomerulosclerosis. In vitro and in vivo studies showed that ICN1 induced apoptosis of podocytes through the activation of p53. Genetic deletion of a Notch transcriptional partner (Rbpj) specifically in podocytes or pharmacological inhibition of the Notch pathway (with a gamma-secretase inhibitor) protected rats with proteinuric kidney diseases. Collectively, our observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target.