Disease relevance of Lrp2

• Absence of megalin expression in knockout mice results in holoprosencephaly, indicating an essential yet unidentified function in forebrain development [1].
• To examine apoM binding to megalin, a recombinant apoM was expressed in Escherichia coli and used in surface plasmon resonance and cell culture studies [2].
• Megalin-/- mice are unable to retrieve the steroid from the glomerular filtrate and develop vitamin D deficiency and bone disease [3].
• Megalin knockout mice manifest abnormalities in epithelial tissues including lung and kidney that normally express the protein and they die perinatally from respiratory insufficiency [4].
• Accordingly, megalin KO mice have primary hypothyroidism [5].

High impact information on Lrp2

• In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females [6].
• (2005) show that resistance (insensitivity) to sex steroid hormones is encountered in animals lacking megalin [7].
• We show that 25-(OH) vitamin D3 in complex with its plasma carrier, the vitamin D-binding protein, is filtered through the glomerulus and reabsorbed in the proximal tubules by the endocytic receptor megalin [3].
• These findings demonstrate a pathway whereby circulating lysosomal enzymes are continuously filtered in glomeruli, reabsorbed by megalin-mediated endocytosis, and transferred into lysosomes to exert their function, providing a major source of enzymes to PCT [8].
• Thus, impaired protein endocytosis caused by invalidation of ClC-5 primarily reflects a trafficking defect of megalin and cubilin in PTC [9].

Chemical compound and disease context of Lrp2

• Although the serological phenotype in megalin-/- mice was not associated with histological alterations or goiter, our results support a major role of megalin in thyroid hormone secretion [10].
• The ability of glycoprotein 330/low density lipoprotein receptor-related protein-2 (LRP-2) to function as a lipoprotein receptor was investigated using cultured mouse F9 teratocarcinoma cells [11].

Biological context of Lrp2

• We used mice with complete or conditional megalin gene inactivation in the embryo to demonstrate that expression of megalin in the neuroepithelium but not in the yolk sac is crucial for brain development [1].
• The results suggest that apoM binds to megalin and that megalin-mediated endocytosis in kidney proximal tubules prevents apoM excretion in the urine [2].
• The present study examines the effect of RAP gene disruption on megalin expression and subcellular distribution in the proximal tubule as well as the effect on tubular protein reabsorption [12].
• METHODS: We used genome-wide expression profiling by microarray technology to detect changes in the gene expression pattern in megalin knockout mouse kidneys and to uncover some of the renal pathways affected by megalin deficiency [13].
• RESULTS: Alterations were identified in several (patho)physiologic processes in megalin-deficient kidneys including the renal vitamin D metabolism, transforming growth factor (TGF)-beta1 signal transduction, lipid transport and heavy metal detoxification [13].

Anatomical context of Lrp2

• LRP2/megalin is required for patterning of the ventral telencephalon [1].
• The lipoprotein receptor megalin is expressed in the visceral endoderm (VE), a polarized epithelium that supplies maternal nutrients to the early mammalian embryo [14].
• The results showed apoM binding to immobilized megalin [dissociation constant (Kd) approximately 0.3-1 microm] and that the apoM was endocytosed by cultured rat yolk sac cells in a megalin-dependent manner [2].
• The possible role of megalin in the developing spinal cord, however, is unknown [15].
• Megalin is expressed in the neuroepithelium during central nervous system (CNS) development [15].

Associations of Lrp2 with chemical compounds

• gp330/megalin, a member of the low density lipoprotein (LDL) receptor gene family, is expressed on the apical surfaces of epithelial tissues, including the neuroepithelium, where it mediates the endocytic uptake of diverse macromolecules, such as cholesterol-carrying lipoproteins, proteases, and antiproteinases [4].
• Evidence for an essential role of megalin in transepithelial transport of retinol [16].
• In this report, we show that the low density lipoprotein receptor (LDLR) gene family member megalin/glycoprotein (gp) 330 is capable of binding and mediating the cellular uptake and degradation of Lp(a) in vitro [17].
• Megalin-mediated reuptake of retinol in the kidneys of mice is essential for vitamin A homeostasis [18].
• A major effect of megalin deficiency, however, was evident in retinyl ester levels in the liver (P < 0.05), which were approximately 37% lower than those in megalin(lox/lox) controls (P < 0.05, Student's t test) during the 84-d period of dietary VA deprivation [18].
• TGF-beta, intercellular adhesion molecule, vascular cellular adhesion molecule, endothelin-1, and cell proliferation were high in megalin-positive cells, whereas apoptosis, heat-shock protein 25, and osteopontin were enhanced in megalin-deficient cells [19].

Physical interactions of Lrp2

• Disabled-2 (Dab2) is a cytoplasmic adaptor protein that binds to the cytoplasmic tail of the multiligand endocytic receptor megalin, abundantly expressed in renal proximal tubules [20].
• Kidney-derived apolipoprotein M binds to megalin, a member of the low-density lipoprotein-receptor family, which interacts with many lipocalins in renal tubuli [21].
• Myoglobin bound to purified megalin and cubilin with Kd values of 2.0 and 3 microM, respectively, as evaluated by surface plasmon resonance analysis [22].

Co-localisations of Lrp2

• In rat yolk sac epithelial BN16 cells, Dab2 was present apically and colocalized with megalin [20].

Regulatory relationships of Lrp2

• During embryonic development, megalin was found to be expressed along the apical surfaces of neuroepithelial cells and was coexpressed with Shh in the ventral floor plate of the neural tube [23].
• Concentration-dependent inhibition by cytochrome c on gentamicin uptake was also observed in OK kidney epithelial cells expressing megalin [24].

Other interactions of Lrp2

• As a consequence of absent SHH activity, ventrally derived oligodendroglial and interneuronal cell populations are lost in the forebrain of megalin-/- embryos [1].
• These studies suggest that Dab2 p96 mediates endocytosis of megalin in the VE [14].
• Low-density lipoprotein receptor-related protein (LRP)-2/megalin is transiently expressed in a subpopulation of neural progenitors in the embryonic mouse spinal cord [15].
• Megalin, a member of the low density lipoprotein receptor gene family, is required for efficient protein absorption in the proximal tubule [25].
• By immunocytochemistry, immunoblotting, and a fluorogenic enzyme assay presenilin-1 (required for gamma-secretase activity) and gamma-secretase activity were found in the brush border of proximal kidney tubules where megalin is localized [25].

Analytical, diagnostic and therapeutic context of Lrp2

• Direct interaction of cathepsin B with megalin was demonstrated by surface plasmon resonance [8].
• Immunoblotting analysis of renal microsomes and opossum kidney proximal tubule (OKP) cells using antibodies directed to the cytosolic domain of megalin showed a 35-40-kDa, membrane-associated, carboxyl-terminal fragment of megalin (MCTF) [25].
• Immunostaining and Western blot analyses demonstrated the uptake of His-sRAP and the accelerated internalization of megalin in proximal tubular cells 1 h after administration [26].
• Megalin expression was reduced to approximately 23% estimated by immunoblotting and supported by immunocytochemistry and by the amount of megalin recovered by RAP affinity chromatography [12].
• We report here in situ hybridization mapping of the corresponding gene, designed as low-density lipoprotein receptor related protein-2 and symbolized as LRP2, to human chromosome region 2q31-->q32.1 and porcine chromosome region 15q22-->q24 [27].

References