Analysis of the functions of the endocytosis receptor megalin and its application to nephrology and regenerative medicine

meggalin是一种内吞作用受体，在近端小管细胞的顶膜中大量表达。它的功能是吸收和降解由肾小球过滤的低分子量蛋白质。我们分析了巨巨苷的功能，并对其在临床肾内科和再生医学中的应用进行了基础研究。主要研究结果如下：1)研究了meggalin在葡萄糖修饰晚期糖基化终产物（AGE）内吞作用中参与糖尿病肾病发病机制的作用。我们发现了一种新的age结合蛋白（参考文献1）。我们完成了该蛋白的鉴定，并正在研究其病理生理相关性。我们还发现meggalin结合羰基化合物修饰的AGE并参与细胞摄取。2)我们报道了一种生物工程植入表达meggalin的肾衰细胞去除β_2-微球蛋白的治疗模型，β_2-微球蛋白是一种引起透析相关淀粉样变性的尿毒症毒素蛋白（参考文献2）。我们发现meggalin在人羊膜细胞中表达，用于溶菌酶缺乏症的临床植入治疗。3)我们发现瘦素（一种假定的尿毒症毒素蛋白）的肾脏代谢是由巨噬蛋白介导的，而不是由瘦素受体介导的。我们用石英晶体微天平分析了巨噬蛋白与瘦素的结合亲和力。4)我们在遗传性低分子蛋白尿的登特病中发现了一种新的CLCN5基因突变，并在肾活检标本中发现了巨噬细胞肽的肾脏表达降低。5)为了在肾衰竭中诱导meggalin的肝脏基因表达，我们开发了一种在基底外细胞膜中表达meggalin的策略（文献3）。

Megalin is an endocytosis receptor that is expressed abundantly in the apical membranes of proximal tubule cells. It functions for absorption and degradation of low-molecular-weight proteins filtered by glomeruli. We analyzed the functions of megalin and carried out basic studies for its application to clinical nephrology and regenerative medicine. The main research results are as follows :1)We investigated the role of megalin in the endocytosis of glucose-modified advanced glycation end products(AGE) that participate in the pathogenesis of diabetic nephropathy. We and the presence of a novel AGE-binding protein (ref.1). We completed the identification of the protein and are in the process of studying its pathophysiological relevance. We also found that megalin binds carbonyl compound-modified AGE and is involved in the cellular uptake.2)We reported a therapeutic model for bioengineered implantation of megalin-expressing cells in renal failure to remove β_2-microglobulin, a uremic toxin protein inducing dialysis-related amyloidosis (ref.2). We identified that megalin is expressed in the human amniotic cells that have been used for clinical implantation therapies for lysozomal enzyme deficiency.3)We found that the renal metabolism of leptin, a putative uremic toxin protein, is mediated by megalin but not by the leptin receptors. We analyzed the binding affinity of megalin with leptin using quartz-crystal microbalance.4)We identified a novel CLCN5 gene mutation in Dent' disease with hereditary low-molecular-weight proteinuria, and revealed decreased renal expression of megalin in the kidney biopsy specimens.5)To induce hepatic gene expression of megalin in renal failure, we developed a strategy to express megalin in the basolateral cellular membrances (ref.3).