Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte.
Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte.
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DOI：
10.1038/srep43921
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发表时间：
2017-03-07
影响因子：
4.6
通讯作者：
Asanuma K
中科院分区：
文献类型：
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作者：
Sasaki Y;Hidaka T;Ueno T;Akiba-Takagi M;Oliva Trejo JA;Seki T;Nagai-Hosoe Y;Tanaka E;Horikoshi S;Tomino Y;Suzuki Y;Asanuma K
肾小球硬化改变的不可逆性取决于足细胞损伤的程度。我们先前已经证明了在严重损伤的足细胞中podocin的内吞移位到亚细胞区域，并且发现该过程是主要的疾病触发因素。在这里，我们确定了蛋白分选连接蛋白9（SNX 9）作为一种新的促进podocin内吞作用在酵母双杂交分析。SNX 9参与网格蛋白介导的内吞作用、肌动蛋白重排和囊泡转运调节。我们的结果揭示并证实了SNX 9仅通过SNX 9的Bin-Amphiphysin-Rvs（BAR）结构域与podocin相互作用。免疫荧光染色显示SNX 9的表达在足细胞阿霉素诱导的损伤在体外和体内。最后，对人肾小球疾病活检样品的分析表明，在代表严重足细胞损伤的样品中，如预后不良的伊加肾病、膜性肾病和局灶节段性肾小球硬化症，SNX 9表达强烈，并与podocin共定位。总之，我们鉴定了SNX 9作为严重足细胞损伤中足蛋白内吞作用的促进剂，并证明了SNX 9在肾病模型小鼠和患有不可逆肾小球疾病的人类患者的足细胞中的表达。
The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury. We have previously demonstrated the endocytic translocation of podocin to the subcellular area in severely injured podocytes and found that this process is the primary disease trigger. Here we identified the protein sorting nexin 9 (SNX9) as a novel facilitator of podocin endocytosis in a yeast two-hybrid analysis. SNX9 is involved in clathrin-mediated endocytosis, actin rearrangement and vesicle transport regulation. Our results revealed and confirmed that SNX9 interacts with podocin exclusively through the Bin–Amphiphysin–Rvs (BAR) domain of SNX9. Immunofluorescence staining revealed the expression of SNX9 in response to podocyte adriamycin-induced injury both in vitro and in vivo. Finally, an analysis of human glomerular disease biopsy samples demonstrated strong SNX9 expression and co-localization with podocin in samples representative of severe podocyte injury, such as IgA nephropathy with poor prognosis, membranous nephropathy and focal segmental glomerulosclerosis. In conclusion, we identified SNX9 as a facilitator of podocin endocytosis in severe podocyte injury and demonstrated the expression of SNX9 in the podocytes of both nephropathy model mice and human patients with irreversible glomerular disease.