Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease.
Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease.
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Flot2 作为蛋白尿肾病足细胞损伤的新型介质
DOI：
10.7150/ijbs.78945
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发表时间：
2023
影响因子：
9.2
通讯作者：
Shi W
中科院分区：
文献类型：
--
作者：
Yu C;Zhang H;Liu S;Li R;Zhao X;Chen Y;Li Z;Ma J;Wang W;Ye Z;Liang X;Zhang L;Shi W
足细胞损伤是慢性肾脏病（CKD）的常见标志。podocin-nephrin复合物定位于足细胞的脂筏中，对减少足细胞损伤和蛋白尿至关重要，然而其定位的机制尚不清楚。这项研究揭示了Flot2在稳定位于脂筏中的podocin-nephrin复合物中的重要作用。我们首次证实了Flot2在足细胞中表达，并证实足细胞特异性Flot2缺失加重了LPS/ADR诱导的肾病小鼠模型的蛋白尿、足细胞损伤和肾小球病理。同时，足细胞特异性Flot2过表达转基因小鼠在LPS或ADR攻击时，足细胞损伤、蛋白尿和病理异常得到预防。进一步发现Flot2对于将podocin和nephrin募集到筏中并改善足细胞损伤至关重要。Flot2和podocin通过它们的SPFH结构域直接相互作用。同时，我们还发现Flot-2是Krüppel样因子（KLF 15）的直接靶点。重要的是，我们观察到Flot2在足细胞病变患者的肾活检中下调，其表达与蛋白尿呈负相关，与eGFR呈正相关，表明Flot2可能是蛋白尿性肾病的新治疗靶点。
Podocyte injury is a common hallmark of chronic kidney disease (CKD). The podocin-nephrin complex localized in lipid rafts of podocyte is vital to reduce podocyte injury and proteinuria, however, the mechanism underlying its localization remains unclear. This study uncovers an important role of Flot2 in stabilizing the podocin-nephrin complex localized in lipid rafts. We first confirmed that Flot2 was expressed in podocyte and demenstrated that podocyte-specific Flot2 deletion worsen albuminuria, podocyte injury and glomerular pathology in LPS/ADR-induced nephropathy mouse models. Meanwhile, podocyte injury, albuminuria and pathologic aberrance were prevented in podocyte-specific Flot2 overexpression transgenic mice when challenged with LPS or ADR. Further found that Flot2 was vital to recruit podocin and nephrin into rafts and ameliorated podocyte injury. Flot2 and podocin directly interacted with each other via their SPFH domain. Meanwhile, we also showed that Flot-2 is a direct target of Krüppel-like factor (KLF15). Importanly, we observed that Flot2 was downregulated in renal biopsies from patients with podocytopathies and its expression negatively correlated with proteinuria and positively correlated with eGFR, indicating that Flot2 may be a novel therapeutic target for proteinuric kidney disease.
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影响因子：
3.5
作者：
Langhorst, Matthias F.;Solis, Gonzalo P.;Stuermer, Claudia A. O.
通讯作者：
Stuermer, Claudia A. O.
影响因子：
15.9
作者：
Mallipattu, Sandeep K.;Horne, Sylvia J.;He, John C.
通讯作者：
He, John C.
DOI：
10.1097/01.asn.0000060578.79050.e0
发表时间：
2003-05-01
影响因子：
13.6
作者：
Caridi, G;Bertelli, R;Ghiggeri, GM
通讯作者：
Ghiggeri, GM
影响因子：
7.7
作者：
Horne, Sylvia J.;Vasquez, Jessica M.;Mallipattu, Sandeep K.
通讯作者：
Mallipattu, Sandeep K.
影响因子：
3.5
作者：
Huber, TB;Simons, M;Benzing, T
通讯作者：
Benzing, T