Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches.
Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches.
复制标题
通过基因敲除和反义转基因方法深入了解子宫珠蛋白的生理功能。
DOI：
10.1111/j.1749-6632.2000.tb05532.x
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发表时间：
2000
影响因子：
5.2
通讯作者：
Mukherjee,AB
中科院分区：
文献类型：
--
作者：
Zhang,Z;Kundu,GC;Zheng,F;Yuan,CJ;Lee,E;Westphal,H;Ward,J;DeMayo,F;Mukherjee,AB
摘要：为了确定子宫珠蛋白（UG）（一种类固醇诱导的同二聚体分泌蛋白）的生理功能，我们培育了转基因小鼠，这些小鼠要么因 UG 基因敲除（UG-KO）而完全缺乏 UG，要么因 UG 反义 RNA（UG-AS）的表达而部分 UG 缺陷。 UG-KO 和 UG-AS 小鼠均出现免疫球蛋白 A (IgA) 肾病 (IgAN)，其特征是微量血尿、蛋白尿以及 IgA、纤连蛋白 (Fn)、胶原蛋白和 C3 补体的肾小球沉积。 UG-KO 和 UG-AS 小鼠的这种表型实际上与人类 IgAN（世界上最常见的原发性肾小球病）的表型相同。 UG 预防小鼠这种疾病的分子机制似乎集中在 UG 与 Fn 的相互作用上。由于 Fn、IgA 和 UG 存在于循环中，并且在人类 IgAN 中报告了高血浆水平的 IgA-Fn 复合物，因此我们试图确定 UG 是否与 Fn 相互作用并阻止 Fn-Fn 和/或 IgA-Fn 相互作用，这对于 Fn 和 IgA 的异常组织沉积至关重要。我们的免疫共沉淀研究揭示了 Fn-UG 异聚体在体外的形成，并且这些异聚体在正常小鼠的血浆中可检测到，但在 UG-KO 小鼠中却检测不到。此外，在 UG-KO 小鼠中也发现了高血浆水平的 IgA-Fn 复合物（人类 IgAN 患者的特征）。最后，对 UG-KO 小鼠同时给予 UG + Fn 或 UG + IgA 分别阻止 Fn 和 IgA 的肾小球沉积。我们的结果定义了 IgAN 可能的分子机制，并深入了解 UG 在维持小鼠正常肾功能方面的至少一个重要生理功能。
Abstract:To determine the physiological function(s) of uteroglobin (UG), a steroid‐inducible, homodimeric, secreted protein, we have generated transgenic mice that either are completely UG‐deficient due to UG gene‐knockout (UG‐KO) or are partially UG‐deficient due to the expression of UG antisense RNA (UG‐AS). Both the UG‐KO and UG‐AS mice develop immunoglobulin A (IgA) nephropathy (IgAN), characterized by microhematuria, albuminuria, and renal glomerular deposition of IgA, fibronectin (Fn), collagen, and C3 complement. This phenotype of both UG‐KO and UG‐AS mice is virtually identical to that of human IgAN, the most common primary glomerulopathy worldwide. The molecular mechanism by which UG prevents this disease in mice appears to center around UG's interaction with Fn. Since Fn, IgA, and UG are present in circulation and high plasma levels of IgA‐Fn complex have been reported in human IgAN, we sought to determine whether UG interacts with Fn and prevents Fn‐Fn and/or IgA‐Fn interactions, essential for abnormal tissue deposition of Fn and IgA. Our coimmunoprecipitation studies uncovered the formation of Fn‐UG heteromersin vitroand these heteromers are detectable in the plasma of normal mice, but not UG‐KO mice. Further, high plasma levels of IgA‐Fn complex, a characteristic of human IgAN patients, were also found in UG‐KO mice. Finally, coadministration of UG + Fn or UG + IgA to UG‐KO mice prevented glomerular deposition of Fn and IgA, respectively. Our results define a possible molecular mechanism of IgAN and provide insight into at least one important physiological function of UG in maintaining normal renal function in mice.