The Heymann nephritis antigenic complex: megalin (gp330) and RAP.
The Heymann nephritis antigenic complex: megalin (gp330) and RAP.
复制标题
DOI：
--
复制
发表时间：
1995-07
期刊：
影响因子：
--
通讯作者：
M. Farquhar;A. Saito;D. Kerjaschki;R. Orlando
中科院分区：
文献类型：
--
作者：
M. Farquhar;A. Saito;D. Kerjaschki;R. Orlando
Heymann肾炎（HN）自1959年由Heymann首次描述以来，已被广泛研究作为人类膜性肾病的模型。HN是通过用来自近端小管刷状缘的抗原免疫大鼠而以活性形式诱导的，导致上皮下肾小球免疫沉积。正常大鼠注射抗刷状缘抗体也可被动诱发HN。在20世纪70年代，对HN发病机制的理解取得了突破，当时确定该疾病是由于循环抗体与肾小球成分结合所致。这进而导致检索以鉴定内源性抗原。1982年，gp330（现在称为巨蛋白），一种位于肾小球和近端肾小管上皮细胞网格蛋白包被的小坑中的糖蛋白，被确定为靶抗原。1990年，第二种蛋白质（44 kd），现在称为RAP（受体相关蛋白），与巨蛋白结合，也被证明是靶抗原。这两种分子已被克隆和测序，并在正常上皮细胞中的作用已被探索。巨蛋白（gp330）是低密度脂蛋白受体基因家族的成员，作为多配体受体，可摄取多种大分子（纤溶酶原、蛋白酶：蛋白酶抑制剂复合物、富含载脂蛋白E的极低密度脂蛋白、乳铁蛋白等）。RAP与megalin结合，似乎作为伴侣蛋白，协助megalin在内质网中折叠并转运至细胞表面。本文综述了巨蛋白和RAP的结构、功能和运输，以及这两种分子在HN发病机制中的作用。
Heymann nephritis (HN) has been extensively studied as a model of human membranous nephropathy since it was first described by Heymann in 1959. HN was induced in active form by the immunization of rats with antigens derived from the proximal tubule brush border, resulting in subepithelial glomerular immune deposits. HN was also induced passively by the injection of antibrush border antibodies into normal rats. A breakthrough in the understanding of the pathogenesis of HN was made in the 1970s, when it was established that the disease was due to the binding of circulating antibodies to glomerular components. This in turn led to a search to identify the endogenous antigen(s). In 1982, gp330 (now called megalin), a glycoprotein located in clathrin-coated pits of glomerular and proximal tubular epithelia, was identified as a target antigen. In 1990, a second protein (44 kd), now known as RAP (for receptor associated protein), that binds to megalin was also shown to be a target antigen. Both molecules have been cloned and sequenced, and their role in normal epithelial cells has been explored. It has come to light that megalin (gp330) is a member of the low-density lipoprotein receptor gene family and functions as a multiligand receptor for the uptake of a variety of macromolecules (plasminogen, protease: protease inhibitor complexes, apolipoprotein E-enriched very low-density lipoproteins, lactoferrin, among others). RAP associates with megalin and appears to function as a chaperone assisting in the folding of megalin in the endoplasmic reticulum and its transport to the cell surface. This review considers what is now known about the structure, function, and trafficking of megalin and RAP and the role of these two molecules in the pathogenesis of HN.