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

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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).