Podocyte-specific overexpression of wild type or mutant trpc6 in mice is sufficient to cause glomerular disease.
Podocyte-specific overexpression of wild type or mutant trpc6 in mice is sufficient to cause glomerular disease.
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小鼠中野生型或突变型 trpc6 的足细胞特异性过度表达足以引起肾小球疾病。
DOI：
10.1371/journal.pone.0012859
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发表时间：
2010-09-20
期刊：
影响因子：
3.7
通讯作者：
Walz, Katherina
中科院分区：
文献类型：
--
作者：
Krall, Paola;Canales, Cesar P.;Kairath, Pamela;Carmona-Mora, Paulina;Molina, Jessica;Carpio, J. Daniel;Ruiz, Phillip;Mezzano, Sergio A.;Li, Jing;Wei, Changli;Reiser, Jochen;Young, Juan I.;Walz, Katherina
TRPC6 钙通道（瞬时受体电位通道 6）基因突变与常见的影响儿童和成人的局灶性节段性肾小球硬化症 (FSGS) 相关。此外，获得性肾小球疾病与 TRPC6 表达水平升高相关。然而，TRPC6 在 FSGS 发病机制中的确切作用仍有待阐明。在这项工作中，我们描述了三种不同转基因小鼠品系的产生和表型特征，这些转基因小鼠品系具有野生型或先前与 FSGS 相关的 Trpc6 的两种突变形式（P111Q 和 E896K）中的任何一种的足细胞特异性过度表达。与人类表型一致，在几乎所有转基因品系中都可检测到非肾病范围的白蛋白尿。组织学分析表明，转基因小鼠患上了与人类 FSGS 类似的肾脏疾病。在表达野生型或突变型Trpc6（特别是在足细胞中）的非转基因和转基因小鼠之间，发现肾小球病变存在2-3倍的差异。转基因小鼠肾小球的电子显微镜显示足细胞足突广泛消失。我们得出的结论是，足细胞中 Trpc6（野生型或突变型）的过度表达足以引起与 FSGS 一致的肾脏疾病。我们的结果有助于强化足细胞在 FSGS 病因学中的核心作用。这些小鼠构成了一个重要的新模型，用于研究这种复杂疾病的未来疗法和结果。
Mutations in the TRPC6 calcium channel (Transient receptor potential channel 6) gene have been associated with familiar forms of Focal and Segmental Glomerulosclerosis (FSGS) affecting children and adults. In addition, acquired glomerular diseases are associated with increased expression levels of TRPC6. However, the exact role of TRPC6 in the pathogenesis of FSGS remains to be elucidated. In this work we describe the generation and phenotypic characterization of three different transgenic mouse lines with podocyte-specific overexpression of the wild type or any of two mutant forms of Trpc6 (P111Q and E896K) previously related to FSGS. Consistent with the human phenotype a non-nephrotic range of albuminuria was detectable in almost all transgenic lines. The histological analysis demonstrated that the transgenic mice developed a kidney disease similar to human FSGS. Differences of 2–3 folds in the presence of glomerular lesions were found between the non transgenic and transgenic mice expressing Trpc6 in its wild type or mutant forms specifically in podocytes. Electron microscopy of glomerulus from transgenic mice showed extensive podocyte foot process effacement. We conclude that overexpression of Trpc6 (wild type or mutated) in podocytes is sufficient to cause a kidney disease consistent with FSGS. Our results contribute to reinforce the central role of podocytes in the etiology of FSGS. These mice constitute an important new model in which to study future therapies and outcomes of this complex disease.
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影响因子：
3.7
作者：
Heeringa SF;Möller CC;Du J;Yue L;Hinkes B;Chernin G;Vlangos CN;Hoyer PF;Reiser J;Hildebrandt F
通讯作者：
Hildebrandt F
影响因子：
30.8
作者：
Kopp, Jeffrey B.;Smith, Michael W.;Nelson, George W.;Johnson, Randall C.;Freedman, Barry I.;Bowden, Donald W.;Oleksyk, Taras;McKenzie, Louise M.;Kajiyama, Hiroshi;Ahuja, Tejinder S.;Berns, Jeffrey S.;Briggs, William;Cho, Monique E.;Dart, Richard A.;Kimmel, Paul L.;Korbet, Stephen M.;Michel, Donna M.;Mokrzycki, Michele H.;Schelling, Jeffrey R.;Simon, Eric;Trachtman, Howard;Vlahov, David;Winkler, Cheryl A.
通讯作者：
Winkler, Cheryl A.
影响因子：
4.2
作者：
Kajiyama H;Titus S;Austin CP;Chiotos K;Matsumoto T;Sakairi T;Kopp JB
通讯作者：
Kopp JB
DOI：
10.1097/01.asn.0000059864.88610.5e
发表时间：
2003-05-01
影响因子：
13.6
作者：
Michaud, JL;Lemieux, LI;Kennedy, CRJ
通讯作者：
Kennedy, CRJ
影响因子：
5.3
作者：
Donoviel, DB;Freed, DD;Powell, DR
通讯作者：
Powell, DR