Transcription factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis
Transcription factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis
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DOI：
10.1016/j.kint.2020.02.038
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发表时间：
2020-08-01
影响因子：
19.6
通讯作者：
Takahashi, Satoru
中科院分区：
文献类型：
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作者：
Usui, Toshiaki;Morito, Naoki;Takahashi, Satoru
局灶节段性肾小球硬化症（FSGS）是类固醇抵抗性肾病综合征的常见原因。 FSGS 的自发缓解很少见，并且类固醇耐药的 FSGS 经常进展为肾功能衰竭。 FSGS 的许多遗传形式已被描述，这些形式是由对足细胞功能很重要的蛋白质突变引起的。在这里，我们证明了一种基本的亮氨酸拉链转录因子 MafB 可以预防 FSGS。发现 FSGS 患者足细胞中 MAFB 表达减少。此外，条件性足细胞特异性 MafB 敲除小鼠出现 FSGS，伴有大量蛋白尿，并伴有裂隙隔膜相关蛋白（Nphs1 和 Magi2）和足细胞特异性转录因子 Tcf21 的耗竭。这些发现表明 MafB 在 FSGS 的发病机制中发挥着至关重要的作用。与此一致的是，MafB 足细胞特异性转基因小鼠的足细胞中 MafB 过度表达可改善阿霉素诱导的 FSGS 和随之而来的蛋白尿。因此，MafB可能成为FSGS的新治疗靶点。
Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome. Spontaneous remission of FSGS is rare and steroid-resistant FSGS frequently progresses to renal failure. Many inheritable forms of FSGS have been described, caused by mutations in proteins that are important for podocyte function. Here, we show that a basic leucine zipper transcription factor, MafB, protects against FSGS. MAFB expression was found to be decreased in the podocytes of patients with FSGS. Moreover, conditional podocyte-specific MafB-knockout mice developed FSGS with massive proteinuria accompanied by depletion of the slit diaphragm-related proteins (Nphs1 and Magi2), and the podocyte-specific transcription factor Tcf21. These findings indicate that MafB plays a crucial role in the pathogenesis of FSGS. Consistent with this, adriamycin-induced FSGS and attendant proteinuria were ameliorated by MafB overexpression in the podocytes of MafB podocyte-specific transgenic mice. Thus, MafB could be a new therapeutic target for FSGS.