Zinc fingers and homeoboxes (ZHX) proteins are heterodimeric transcriptional factors largely expressed at the cell membrane in podocytes in vivo. We found ZHX2-based heterodimers in podocytes, with ZHX2-ZHX1 predominantly at the cell membrane of the podocyte cell body, and ZHX2-ZHX3 at the slit diaphragm. In addition to changes in overall ZHX2 expression, there was increased podocyte nuclear ZHX3 and ZHX2 in patients with focal segmental glomerulosclerosis, and increased podocyte nuclear ZHX1 in patients with minimal change disease. Zhx2 deficient mice had increased podocyte ZHX1 and ZHX3 expression. Zhx2 deficient mice and podocyte specific Zhx2 overexpressing transgenic rats develop worse experimental focal segmental glomerulosclerosis than controls, with increased nuclear ZHX3 and ZHX2, respectively. By contrast, podocyte specific Zhx2 overexpressing transgenic rats develop lesser proteinuria during experimental minimal change disease due to peripheral sequestration of ZHX1 by ZHX2. Using co-immunoprecipitation, the interaction of ZHX2 with aminopeptidase A in the podocyte body cell membrane, and EPHRIN B1 in the slit diaphragm were noted to be central to upstream events in animal models of minimal change disease and focal segmental glomerulosclerosis, respectively. Mice deficient in Enpep, the gene for aminopeptidase A, and Efnb1, the gene for ephrin B1 developed worse albuminuria in glomerular disease models. Targeting aminopeptidase A in Zhx2 deficient mice with monoclonal antibodies induced albuminuria and upregulation of the minimal change disease mediator angiopoietin-like 4 through nuclear entry of ZHX1. Thus, podocyte ZHX2 imbalance is a critical factor in human glomerular disease, with minimal change disease disparities mediated mostly through ZHX1, and focal segmental glomerulosclerosis deviations through ZHX3 and ZHX2.

中文翻译：

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锌指和同源框 2 蛋白 ZHX2 及其相互作用蛋白调节足细胞疾病的上游通路。

锌指和同源框 (ZHX) 蛋白是异二聚体转录因子，主要在体内足细胞的细胞膜上表达。我们在足细胞中发现了基于 ZHX2 的异二聚体，其中 ZHX2-ZHX1 主要位于足细胞胞体的细胞膜上，而 ZHX2-ZHX3 位于狭缝隔膜上。除了整体 ZHX2 表达的变化外，局灶节段性肾小球硬化患者的足细胞核 ZHX3 和 ZHX2 增加，而微小病变患者的足细胞核 ZHX1 增加。zhx2 缺陷小鼠足细胞 ZHX1 和 ZHX3 表达增加。Zhx2 缺陷小鼠和足细胞特异性 Zhx2 过表达转基因大鼠比对照组发生更严重的实验性局灶节段性肾小球硬化，核 ZHX3 和 ZHX2 分别增加。相比之下，由于 ZHX2 对 ZHX1 的外周隔离，足细胞特异性 Zhx2 过表达转基因大鼠在实验性微小病变疾病期间出现较少的蛋白尿。使用共免疫沉淀，在微小病变疾病和局灶节段性肾小球硬化动物模型中，ZHX2 与足细胞体细胞膜中的氨肽酶 A 和裂隙隔膜中的 EPHRIN B1 的相互作用被认为是上游事件的中心。缺乏 Enpep（氨肽酶 A 的基因）和 Efnb1（ephrin B1 的基因）的小鼠在肾小球疾病模型中出现更严重的蛋白尿。用单克隆抗体靶向 Zhx2 缺陷小鼠中的氨肽酶 A 通过 ZHX1 的核进入诱导白蛋白尿和微小变化疾病介质血管生成素样 4 的上调。因此，