Altered modulation of WNT-β-catenin and PI3K/Akt pathways in IgA nephropathy
Altered modulation of WNT-β-catenin and PI3K/Akt pathways in IgA nephropathy
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DOI：
10.1038/ki.2010.138
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发表时间：
2010-08-01
影响因子：
19.6
通讯作者：
Schena, Francesco P.
中科院分区：
文献类型：
--
作者：
Cox, Sharon N.;Sallustio, Fabio;Schena, Francesco P.
免疫球蛋白A肾病(IgAN)是世界上最常见的原发性肾小球肾炎。基本缺陷存在于IgA免疫系统和外周血白细胞，而不是局部肾脏异常。为了明确导致疾病的细胞内机制，我们进行了一项微阵列研究，以确定从12名IgAN患者和8名健康对照分离的外周血白细胞中差异调节的基因和途径。在IgAN患者和对照组之间差异表达的基因主要涉及典型的WNT-β-catenin和PI3K/Akt通路。我们还检测了从一组独立的IgAN患者和健康对照中分离出来的外周血单核细胞及其亚群。在IgAN患者中，WNT-β-catenin和PI3K/Akt的关键调节因子Inversin和PTEN的蛋白水平较低，提示这些信号通路处于过度激活状态。此外，随着外周血单核细胞增殖率的增加，磷酸化Akt蛋白水平和核β-连环素积聚增加。亚群分析揭示了单核细胞中WNT信号的一个主要异常。因此，这些通路的过度激活可能有助于深入了解IgAN的发病机制。《国际肾脏》(2010年)78396407DOI：10.1038/ki.2010.138；2010年5月19日在线发布
Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The basic defect lies within the IgA immune system and in peripheral blood leukocytes, rather than local kidney abnormalities. To define the intracellular mechanisms leading to the disease, we conducted a microarray study to identify genes and pathways differentially modulated in peripheral blood leukocytes isolated from 12 IgAN patients and 8 healthy controls. The genes whose expression discriminated between the IgAN patients and controls were primarily involved in canonical WNT-beta-catenin and PI3K/Akt pathways. We also tested peripheral blood mononuclear cells and their subpopulations isolated from an independent group of IgAN patients and healthy controls. There were low protein levels of inversin and PTEN, key regulators of WNT-beta-catenin and PI3K/Akt, in IgAN patients, suggesting hyperactivation of these pathways. Also, there were increased phospho-Akt protein levels and nuclear beta-catenin accumulation with an enhanced peripheral blood mononuclear cell proliferation rate. Subpopulation analysis uncovered a major irregularity of WNT signaling in monocytes. Hence, hyperactivation of these pathways may provide insight into mechanisms contributing to the pathogenesis of IgAN. Kidney International (2010) 78, 396-407; doi:10.1038/ki.2010.138; published online 19 May 2010