Development of immunoglobulin A nephropathy-like disease in β-1,4-galactosyltransferase-I-deficient mice
Development of immunoglobulin A nephropathy-like disease in β-1,4-galactosyltransferase-I-deficient mice
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DOI：
10.2353/ajpath.2007.060559
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发表时间：
2007-02-01
影响因子：
6
通讯作者：
Asano, Masahide
中科院分区：
文献类型：
--
作者：
Nishie, Toshikazu;Miyaishi, Osamu;Asano, Masahide
β 4糖蛋白的半乳糖基化;在蛋白质构象、稳定性、运输和从循环中清除中起重要作用。最近的研究表明，异常的糖基化导致各种人类疾病。在这里，我们报告了缺乏β-1，4-半乳糖基转移酶（β 4GalT）-I的小鼠，该酶将半乳糖转移到β-1，4键中N-和O-连接聚糖的末端N-乙酰葡糖胺，自发地发展为人免疫球蛋白A肾病（IgAN）样肾小球病变，伴伊加沉积和系膜基质扩张。β 4GaIT-I缺陷小鼠也表现出高血清伊加水平，如人IgAN中的聚合物形式增加。IgAN是肾小球肾炎的最常见形式，并且显著比例的患者进展为肾衰竭。然而，IgAN的病理分子机制知之甚少。在人类中，血清伊加的异常特征，特别是在其铰链区具有异常半乳糖基化和O-聚糖唾液酸化的血清IgA 1被认为有助于IgAN的发病。小鼠伊加具有N-聚糖但不具有O-聚糖，并且来自β 4 GalT-I缺陷小鼠的血清伊加上的N-聚糖的β 4-半乳糖基化和唾液酸化完全不存在。这是第一份证明蛋白质糖基化的遗传重塑导致IgAN的报告。我们认为血清伊加中的碳水化合物参与了IgAN的发展，无论是O-聚糖还是N-聚糖。
beta 4 Galactosylation of glycoproteins; plays important roles hi protein conformation, stability, transport, and clearance from the circulation. Recent studies have revealed that aberrant glycosylation causes various human diseases. Here we report that mice lacking beta-1,4-galactosyltransferase (beta 4GalT)-I, which transfers galactose to the terminal N-acetylglucosamine of N- and O-linked glycans, in a beta-1,4 linkage, spontaneously developed human immunoglobulin A nephropathy (IgAN)-like glomerular lesions with IgA deposition and expanded mesangial matrix. beta 4GaIT-I-deficient mice also showed high serum IgA levels with increased polymeric forms as in human IgAN. IgAN is the most common form of glomerulonephritis, and a significant proportion of patients progress to renal failure. However, pathological molecular mechanisms of IgAN are poorly understood. in humans, abnormal character of serum IgA, especially serum IgA1 with aberrant galactosylation and sialylation of O-glycans in its hinge region is thought to contribute to the pathogenesis of IgAN. Mouse IgA has N-glycans but not O-glycans, and beta 4-galactosylation and sialylation of the N-glycans on the serum IgA from beta 4GalT-I-deficient mice was completely absent. This is the first report demonstrating that genetic remodeling of protein glycosylation causes IgAN. We propose that carbohydrates of serum IgA are involved in the development of IgAN, whether the carbohydrates are O-glycans or N-glycans.