Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes.
Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes.
复制标题
DOI：
10.1038/srep13647
复制
发表时间：
2015-09-18
影响因子：
4.6
通讯作者：
Mikulak J
中科院分区：
文献类型：
--
作者：
Alfano M;Cinque P;Giusti G;Proietti S;Nebuloni M;Danese S;D'Alessio S;Genua M;Portale F;Lo Porto M;Singhal PC;Rastaldi MP;Saleem MA;Mavilio D;Mikulak J
可溶性尿激酶型纤溶酶原激活物受体（suPAR）的血浆水平升高与局灶节段性肾小球硬化（FSGS）有关。此外，不同的临床研究观察到，在各种肾小球疾病和其他人类肾病综合征（如HIV和汉坦病毒感染）、糖尿病和心血管疾病中，suPAR浓度增加。在这里，我们表明，suPAR诱导nephrin下调人类足细胞。这种现象仅由全长suPAR介导，具有时间和剂量依赖性，并与Wilms肿瘤1（WT-1）转录因子表达的抑制有关。此外，αvβ3整合素的拮抗剂RGDfv阻断了suPAR诱导的nephrin抑制。这些体外数据在体内uPAR敲除Plaur−/−小鼠模型中得到证实，证明输注suPAR抑制足细胞中nephrin和WT-1的表达并诱导蛋白尿。这项研究揭示了全长suPAR与足细胞上表达的αvβ3整联蛋白的相互作用导致nephrin的下调，这可能影响以suPAR浓度增加为特征的不同人类病理学中的肾功能。
Increased plasma level of soluble urokinase-type plasminogen activator receptor (suPAR) was associated recently with focal segmental glomerulosclerosis (FSGS). In addition, different clinical studies observed increased concentration of suPAR in various glomerular diseases and in other human pathologies with nephrotic syndromes such as HIV and Hantavirus infection, diabetes and cardiovascular disorders. Here, we show that suPAR induces nephrin down-modulation in human podocytes. This phenomenon is mediated only by full-length suPAR, is time-and dose-dependent and is associated with the suppression of Wilms’ tumor 1 (WT-1) transcription factor expression. Moreover, an antagonist of αvβ3 integrin RGDfv blocked suPAR-induced suppression of nephrin. These in vitro data were confirmed in an in vivo uPAR knock out Plaur−/− mice model by demonstrating that the infusion of suPAR inhibits expression of nephrin and WT-1 in podocytes and induces proteinuria. This study unveiled that interaction of full-length suPAR with αvβ3 integrin expressed on podocytes results in down-modulation of nephrin that may affect kidney functionality in different human pathologies characterized by increased concentration of suPAR.