Megalin knockout mice as an animal model of low molecular weight proteinuria

Megalin is an endocytic receptor expressed on the luminal surface of the re nal proximal tubules, The receptor is believed to play an important role in the tubular uptake of macromolecules filtered through the glomerulus, To e lucidate the role of megalin in vine and to identify its endogenous ligands , we analyzed the proximal tubular function in mice genetically deficient f or the receptor. We demonstrate that megalin-deficient mice exhibit a tubul ar resorption deficiency and excrete low molecular weight plasma proteins i n the urine (low molecular weight protein-uria). Proteins excreted include small plasma proteins that carry lipophilic compounds including vitamin D-b inding protein, retinol-binding protein, alpha(1)-microglobulin and odorant -binding protein. Megalin binds these proteins and mediates their cellular uptake. Urinary loss of carrier proteins in megalin-deficient mice results in concomitant loss of lipophilic vitamins bound to the carriers. Similar t o megalin knockout mice, patients with low molecular weight proteinuria as in Fanconi syndrome are also shown to excrete vitamin/carrier complexes. Th us, these results identify a crucial role of the proximal tubule in retriev al of filtered vitamin/carrier complexes and the central role played by meg alin in this process.