Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure
Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure
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DOI：
10.1681/asn.2014090916
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发表时间：
2016-01-01
影响因子：
13.6
通讯作者：
Campbell, Kirk N.
中科院分区：
文献类型：
--
作者：
Schwartzman, Monica;Reginensi, Antoine;Campbell, Kirk N.
FSGS是美国ESRD最常见的原发性肾小球疾病，在全球范围内发病率正在增加。FSGS是由足细胞损伤引起的，但疾病发病机制的细节仍不清楚。这导致在治疗FSGS和其他蛋白尿肾病中对细胞特异性疗法的临床需求未得到满足。我们以前确定的是相关蛋白（雅普）作为一个促生存的信号分子，在体外沉默增加足细胞对凋亡刺激的敏感性。雅普是一种有效的癌基因，是化疗药物开发的重要靶点。在这项研究中，我们测试了这样一个假设，即足细胞特异性缺失雅普通过增加足细胞凋亡导致蛋白尿性肾病。雅普选择性沉默足细胞使用Cre介导的重组控制的podocin启动子。足细胞中的雅普沉默导致足细胞凋亡、足细胞耗竭、蛋白尿和血清肌酐增加。组织学上表现为系膜硬化、足细胞足突消失、肾小管萎缩、间质纤维化和管型改变。在人原发性FSGS中，我们注意到雅普的球神经表达减少。总之，这些结果表明雅普作为足细胞凋亡的生理拮抗剂的作用，其信号传导对于维持肾小球滤过屏障的完整性是必不可少的。这些数据表明，针对抑制雅普功能的策略具有潜在的肾毒性。进一步的研究应评估雅普在蛋白尿性肾小球神经疾病发病机制中的作用及其作为治疗靶点的潜在效用。
FSGS Is the most common primary glomerular disease underlying ESRD in the United States and is increasing in incidence globally. FSGS results from podocyte injury, yet the mechanistic details of disease pathogenesis remain unclear. This has resulted in an unmet clinical need for cell-specific therapy in the treatment of FSGS and other proteinuric kidney diseases. We previously identified Yes-associated protein (YAP) as a prosurvival signaling molecule, the in vitro silencing of which increases podocyte susceptibility to apoptotic stimulus. YAP is a potent oncogene that is a prominent target for chemotherapeutic drug development. In this study, we tested the hypothesis that podocyte-specific deletion of Yap leads to proteinuric kidney disease through increased podocyte apoptosis. Yap was selectively silenced in podo-cytes using Cre-mediated recombination controlled by the podocin promoter. Yap silencing in podocytes resulted in podocyte apoptosis, podocyte depletion, proteinuria, and an increase in serum creatinine. Histologically, features characteristic of FSGS, including mesangial sclerosis, podocyte foot process effacement, tubular atrophy, interstitial fibrosis, and casts, were observed. In human primary FSGS, we noted reduced glonnerular expression of YAP. Taken together, these results suggest a role for YAP as a physiologic antagonist of podocyte apoptosis, the signaling of which is essential for maintaining the integrity of the glomerular filtration barrier. These data suggest potential nephrotoxicity with strategies directed toward inhibition of YAP function. Further studies should evaluate the role of YAP in proteinuric glonnerular disease pathogenesis and its potential utility as a therapeutic target.