Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys
Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys
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DOI：
10.1681/asn.2014040405
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发表时间：
2015-10-01
影响因子：
13.6
通讯作者：
He, John Cijiang
中科院分区：
文献类型：
--
作者：
Li, Xuezhu;Chuang, Peter Y.;He, John Cijiang
在肾脏发育过程中，需要Nephrin用于足细胞的成熟和裂膈连接复合体的形成。由于nephrin表达在获得性肾小球疾病中下调，因此nephrin缺乏被认为是肾小球损伤的病理特征。然而，nephrin缺乏是否会加重肾小球疾病中的肾小球损伤尚未得到实验证实。在这里，我们产生了诱导型RNA干扰介导的nephrin敲低的小鼠。短期nephrin敲除（6周），在5周龄肾脏发育完成后开始，不影响肾小球结构或功能。相反，长期nephrin敲除（20周）的小鼠出现轻度蛋白尿、足突消失、滤过狭缝变窄、系膜细胞增生和硬化、肾小球基底膜增厚、内皮下带增宽和足细胞凋亡。当受到单侧肾切除术或阿霉素诱导的获得性肾小球损伤时，与没有nephrin敲低的小鼠相比，短期nephrin敲低的小鼠发生了更严重的肾小球损伤。此外，肾蛋白基因敲除小鼠在单侧肾切除术后出现更严重的肾小球增大，多柔比星攻击后出现更多的足细胞凋亡和耗竭。AKT磷酸化，这是一个狭缝隔膜介导的和肾蛋白依赖性途径在足细胞中，显着减少与长期或短期nephrin敲低小鼠单肾切除术或阿霉素挑战。综上所述，我们的数据表明，在基础条件下和获得性肾小球疾病中，需要nephrin来维持裂膜完整性和裂膜介导的信号传导，以保护成年小鼠的肾小球功能和足细胞活力。
Nephrin is required during kidney development for the maturation of podocytes and formation of the slit diaphragm junctional complex. Because nephrin expression is downregulated in acquired glomerular diseases, nephrin deficiency is considered a pathologic feature of glomerular injury. However, whether nephrin deficiency exacerbates glomerular injury in glomerular diseases has not been experimentally confirmed. Here, we generated mice with inducible RNA interference mediated nephrin knockdown. Short-term nephrin knockdown (6 weeks), starting after the completion of kidney development at 5 weeks of age, did not affect glomerular structure or function. In contrast, mice with long-term nephrin knockdown (20 weeks) developed mild proteinuria, foot process effacement, filtration slit narrowing, mesangial hypercellularity and sclerosis, glomerular basement membrane thickening, subendothelial zone widening, and podocyte apoptosis. When subjected to an acquired glomerular insult induced by unilateral nephrectomy or doxorubicin, mice with short-term nephrin knockdown developed more severe glomerular injury compared with mice without nephrin knockdown. Additionally, nephrin-knockdown mice developed more exaggerated glomerular enlargement when subjected to unilateral nephrectomy and more podocyte apoptosis and depletion after doxorubicin challenge. AKT phosphorylation, which is a slit diaphragm mediated and nephrin-dependent pathway in the podocyte, was markedly reduced in mice with long-term or short-term nephrin knockdown challenged with uninephrectomy or doxorubicin. Taken together, our data establish that under the basal condition and in acquired glomerular diseases, nephrin is required to maintain slit diaphragm integrity and slit diaphragm mediated signaling to preserve glomerular function and podocyte viability in adult mice.