Megalin Knockout Mice as an Animal Model of Low Molecular Weight Proteinuria

Abstract

Megalin is an endocytic receptor expressed on the luminal surface of the renal proximal tubules. The receptor is believed to play an important role in the tubular uptake of macromolecules filtered through the glomerulus. To elucidate the role of megalin in vivo and to identify its endogenous ligands , we analyzed the proximal tubular function in mice genetically deficient for the receptor. We demonstrate that megalin-deficient mice exhibit a tubular resorption deficiency and excrete low molecular weight plasma proteins in the urine (low molecular weight proteinuria). The proximal tubules in the kidney are responsible for the retrieval of solutes that have been filtered through the glomerulus. This reuptake pathway selectively captures essential low molecular weight metabolites which pass freely through the glomerular membranes and which would otherwise be lost in the urine. Besides water, the main blood constituents taken up in the proximal tubules are ions, glucose, and amino acids. In addition, small plasma proteins (Ͻ70 kd) are also filtered through the glomerulus and reabsorbed in the proximal tubules. These include plasma carrier proteins (eg, retinol-binding protein), peptide hormones (eg, insulin, parathyroid hormone), and lysozyme.

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

“…Through APPL1, OCRL can be linked to the small scaffold protein GIPC and thus to megalin [11], the scavenger receptor which in kidney mediates the uptake of low molecular weight proteins [19]. Genetic disruption of both GIPC and megalin in mice yields low molecular weight proteinuria, a defect also seen in Lowe Syndrome and Dent Disease [20,21]. Additionally, APPL1 could link OCRL to TrkA, which could help explain the cognitive manifestations of Lowe Syndrome [11,22,23].…”

Localization, mechanism and reduction of renal retention of technetium‐99m labeled epidermal growth factor receptor‐specific nanobody in mice

“…Cells were grown at 378C in a humidified air incubator equilibrated with 5% CO 2 . Female megalin-deficient and megalinexpressing mice were developed in the laboratory of Professor Thomas Willnow (21,22); they were bred and PCR screened in the laboratory of Professor Otto Boerman. Healthy male (ICR/CD1) mice were purchased from Harlan (Horst, The Netherlands).…”

Cellular uptake of steroid carrier proteins—Mechanisms and implications

“…Apart form apolipoprotein (apo) B100 and apoE, potential ligands included proteases and protease inhibitors, enzymes, and peptide hormones (reviewed in Willnow et al, 1999)). A clue as to the true ligands of this receptor came with the analysis of mice with ubiquitous or kidney-specific megalin gene defects (Leheste et al, 1999;Nykjaer et al, 1999). Based on the prominent expression of megalin on the luminal surface of the renal proximal tubules, a role for the receptor in A c c e p t e d M a n u s c r i p t 10 were low-molecular weight carrier proteins including DBP , clara cell secretory protein (CCSP) ), a carrier for progesterone, as well as transcobalamin and retinol binding protein, carriers for vitamin B12 and retinol, respectively .…”