Analysis of physiological and pathophysiological functions of megalin in the proximal tubules and clinical application of its molecular features

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Megalin is a large glycoprotein belonging to the LDL receptor gene family. It is abundantly expressed at the apical membrane of proximal tubule cells and functions as an endocytic scavenger receptor for reabsorbing and metabolizing various ligand proteins filtered by glomeruli.Using yolk sac tumor-derived L2 cells that express megalin abundantly, we identified megalin as being an endocytic receptor mediating cellular uptake and metabolism of β_2-microglobulin, a uremic toxin protein. In patients with endstage renal disease β_2-m accumulates in serum and causes dialysis-related amyloidosis(DRA). To apply the molecular function to clinical practice for β_2-m removal We developed a system for subcutaneous implantation of megalin-expressing cells in renal failure animals. This system would be a novel tissue engineering strategy to compensate for the limitations of current dialysis therapy and improve the survival and quality of life of dialysis patients.We also investigated the role of megalin in cellular uptake and metabolism of advanced glycation endproducts (AGEs). AGEs are generated excessively in diabetes. The low-molecular-weight forms are filtered by glomeruli and reabsorbed and metabolized by proximal tubule cells ; the processes are likely associated with the pathogenesis of diabetic nephropathy, especially of the tubulointerstitial injury. Also, AGEs accumulate in serum of uremic patients and are involved in the pathogenesis of DRA and athelosclerosis in those. Using the L2 cell system, we found that megalin mediates cellular uptake and metabolism of AGEs. We also identified a novel AGE binding protein in the cells which interacts with megalin.In association with the researches described above, we also investigated the other molecular mechanisms of progression of renal diseases.