Deficiency of a Transcriptional Regulator, Inhibitor of Differentiation 3, Induces Glomerulonephritis in Apolipoprotein E-Deficient Mice A Model Linking Hyperlipidemia and Renal Disease
Deficiency of a Transcriptional Regulator, Inhibitor of Differentiation 3, Induces Glomerulonephritis in Apolipoprotein E-Deficient Mice A Model Linking Hyperlipidemia and Renal Disease
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DOI：
10.1016/j.ajpath.2011.04.029
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发表时间：
2011-08-01
影响因子：
6
通讯作者：
McNamara, Coleen
中科院分区：
文献类型：
--
作者：
Bagavant, Harini;Scindia, Yogesh;McNamara, Coleen
高脂血症和肾脏疾病之间的临床联系是很明确的，但高脂血症作为肾脏疾病的原因是罕见的。载脂蛋白e缺陷（ApoE(-/-)）小鼠发展为高脂血症，是动脉粥样硬化的模型。引入缺乏分化抑制剂3 (Id3) ApoE（-/-）的小鼠进一步加剧动脉粥样硬化。ID3是一种在多种细胞类型中表达的转录调节因子。Id3（-/-）小鼠产生针对自身抗原的抗体和唾液腺自身免疫。本研究旨在探讨高脂血症、自身免疫和肾脏疾病之间的联系。研究不同年龄ApoE（-/-）、Id3（-/-）和ApoE(-/-)Id3（-/-）双敲除（DKO）小鼠肾脏病理特征和功能。分析血清样本是否存在自身抗体。16周时，DKO小鼠出现血管增生性肾小球肾炎（GN），导致严重的蛋白尿。GN与肾小球脂质沉积和免疫复合物以及巨噬细胞浸润有关。DKO小鼠有高水平的循环自身抗体。尽管ApoE（-/-）小鼠有肾小球脂质沉积，而Id3（-/-）小鼠有循环自身抗体，但两组年龄匹配的单基因敲除小鼠均未发生GN。这些数据为高脂血症肾脏疾病的诱导是由其他因素决定的假设提供了支持。我们的研究表明，其中一些因素是由ID3调节的。因此，ID3是一种与心血管和肾脏疾病相关的新的危险因素。（中华病理学杂志，2011,179:651-660;DOI: 10.1016/ j.j ajpath.2011.04.029）
The clinical association between hyperlipidemia and renal disease is well established, yet hyperlipidemia as a cause for renal disease is rare. Apolipoprotein E-deficient (ApoE(-/-)) mice develop hyperlipidemia and are a model for atherosclerosis. Introducing deficiency of inhibitor of differentiation 3 (Id3) ApoE(-/-) mice further exacerbates atherosclerosis. ID3 is a transcription regulator expressed in multiple cell types. Id3(-/-) mice develop antibodies to self-antigens and salivary gland autoimmunity. This study was undertaken to investigate a link between hyperlipidemia, autoimmunity, and renal disease. ApoE(-/-), Id3(-/-) and ApoE(-/-)Id3(-/-) double-knockout (DKO) mice were studied at different ages for renal pathological features and function. Serum samples were analyzed for the presence of autoantibodies. At 16 weeks, DKO mice developed mesangioproliferative glomerulonephritis (GN), leading to severe proteinuria. GN was associated with glomerular deposition of lipids and immune complexes and with macrophage infiltration. DKO mice had high levels of circulating autoantibodies. Although ApoE(-/-) mice had glomerular lipid deposits and Id3(-/-) mice had circulating autoantibodies, neither group of age-matched single-knockout mice developed GN. These data provide support for the hypothesis that induction of renal disease in hyperlipidemia is dictated by additional factors. Our study shows that some of these factors are regulated by ID3. Thus, ID3 is a novel risk factor linking cardiovascular and renal disease. (Am J Pathol 2011, 179:651-660; DOI: 10.1016/j.ajpath.2011.04.029)