Ultrastructural localization of megalin in the rat cochlear duct

Mizuta, Kunihiro; Saito, Akihiko; Watanabe, Takahiro; Nagura, Mitsuyoshi; Arakawa, Masaaki; Shimizu, Fujio; Hoshino, Tomoyuki

doi:10.1016/s0378-5955(98)00221-4

Cited by 50 publications

(43 citation statements)

References 32 publications

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“…In addition to the tectorial membrane, the marginal cells of the stria vascularis, the epithelial cells of Reissner's membrane, and the epithelial cells of the spiral prominence were also stained with mAb2E12. These results are consistent with those described previously for cochlea epithelial cells obtained using immunogold electron microscopy, in which megalin was localized in the apical vesicles of these cells, and its localization pattern resembled that in kidney proximal tubules (Mizuta et al, 1999). Previous studies have suggested that the ES promotes homeostasis in the membranous labyrinth by the regulation of endolymph volume and the elimination of endolymph debris (Thalmann and Thalmann, 1999).…”

Section: Discussionsupporting

confidence: 92%

“…Kounnas et al (1994) demonstrated that the inner ear epithelia of embryonic mice expressed megalin. Using immunogold electron microscopy, Mizuta et al (1999) demonstrated that megalin was localized in the epithelial cells of the rat cochlear duct, a part of the endolymphatic compartment of the inner ear. It was previously reported that ES epithelial cells could take up several macromolecule tracers introduced from the cochlear duct or by direct injection (Fukazawa et al, 1990;Fukazawa et al, 1991;Furuta et al, 1992;Hoshikawa et al, 1994;Kakigi et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Soluble Megalin Is Accumulated in the Lumen of the Rat Endolymphatic Sac

Ishida

Hatae

Nishi

et al. 2006

Cell Struct. Funct.

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ABSTRACT. The endolymphatic sac (ES) is believed to play an important role in maintaining homeostasis in the inner ear by the absorption and endocytosis of endolymph. Megalin is a 600-kDa multiligand endocytic receptor expressed in certain types of absorptive epithelia including kidney proximal tubules. We analyzed the immunoreactivity for megalin in rat ES by immunofluorescence, immunogold electron microscopy, and immunoblotting. With immunostaining, the luminal substances of the ES were strongly stained for megalin. Megalin was also localized in luminal macrophage-like cells and both types of epithelial cell (mitochondria-rich cells and ribosomerich cells). In these cells, the megalin was localized in the lumen of endosomes, but was not membrane associated. This localization pattern indicates that the megalin in these cells is not a membrane receptor, but merely one of the constituents that are endocytosed from the lumen of the ES. Immunoblotting indicated that the megalin in the ES is a 210-kDa molecule lacking a cytoplasmic domain. This suggests that the megalin in the ES may be a soluble form, different from the 600-kDa membrane-bound receptor expressed in kidneys. Taken together, it is likely that the megalin in the ES lumen is a soluble component and may be endocytosed by the ES epithelial cells. Furthermore, we found that the tectorial membrane, an acellular structure in the cochlea, gave a strong megalin immunoreaction. Since the cochlea is connected to the ES, the megalin may be transported alone or with the components of the tectorial membrane from the cochlea to the ES lumen through longitudinal flow.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Soluble Megalin Is Accumulated in the Lumen of the Rat Endolymphatic Sac

Ishida

Hatae

Nishi

et al. 2006

Cell Struct. Funct.

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“…Megalin is highly expressed in the marginal cells of the stria vascularis and the proximal tubular cells. Mizuta et al 15 examined the localization of megalin using a post-embedding immunogold method in the rat cochlear duct. Labeling was seen predominantly on the apical membrane and subapical vesicles of strial marginal cells.…”

Section: Discussionmentioning

confidence: 99%

Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin

et al. 2007

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Ototoxicity and nephrotoxicity are dose-limiting side effects of cisplatin. Megalin, a member of the low-density lipoprotein receptor family, is highly expressed in renal proximal tubular cells and marginal cells of the stria vascularis of the inner ear -tissues, which accumulate high levels of platinum-DNA adducts. On the assumption that the mechanisms of cisplatin-induced nephro-and ototoxicity involve megalin we analyzed the incidence of the non-synonymous single nucleotide polymorphisms (SNP) rs2075252 and rs4668123 in 25 patients who developed a distinct hearing loss during cisplatin therapy and in 25 patients without hearing impairment after cisplatin therapy. We found no association between cisplatin-induced ototoxicity and any allele of rs4668123 but observed a higher frequency of the A-allele of rs2075252 in the group with hearing impairment than in the group with normal hearing after cisplatin therapy (0.32 versus 0.14) (w 2 ¼ 5.83, Po0.02; odds ratio: 3.45; 95% confidence interval: 1.11-11.2) indicating that SNPs at the megalin gene might impact the individual susceptibility against cisplatin-induced ototoxicity.

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“…The expression of megalin is principally restricted to epithelial cells, specifi cally at the apical surface (Cui et al, 1996;Morales et al, 1996;Willnow et al, 1996;Nielsen et al, 1998;Zheng et al, 1998;Hermo et al, 1999;Mizuta et al, 1999). Interestingly, despite the presence of some putative basolateral sorting motifs in the cytoplasmic domain of megalin, its apical localization depends mainly on sorting information present in this domain of the receptor because its addition to a reporter protein that lacks sorting information drives traffi cking of the reporter to the apical surface of polarized epithelial cells (Marzolo et al, 2003) (Fig.…”

Section: Megalin Structure and Intracellular Traffickingmentioning

confidence: 99%

“…In the adult, megalin expression is restricted in the central nervous system (CNS) to the choroid plexus (Chun et al, 1999;Carro et al, 2005), the ependymal cells of the lateral ventricles (Gajera et al, 2010) and in spinal cord (Wicher et al, 2006). Megalin expression has been reported in the sensory organs, such as the inner ear (Mizuta et al, 1999;Konig et al, 2008) and the eye (Lundgren et al, 1997;Assemat et al, 2005a;Fisher and Howie, 2006). The presence of megalin has been also found in non-epithelial cells, such as a subpopulation of neural progenitors in the embryonic mouse spinal cord (Wicher et al, 2005), oligodendrocytes of the mouse spinal cord (Wicher et al, 2006), retinal ganglion cells (Fitzgerald et al, 2007) and cerebellar granule neurons (Ambjorn et al, 2008).…”

Section: Megalin In the Central Nervous Systemmentioning

confidence: 99%

New Insights into the Roles of Megalin/LRP2 and the Regulation of its Functional Expression

2011

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Since the discovery of the low-density lipoprotein receptor (LDLR) and its association with familial hypercholesterolemia in the early 1980s, a family of structurally related proteins has been discovered that has apolipoprotein E as a common ligand, and the broad functions of its members have been described. LRP2, or megalin, is a member of the LDLR family and was initially called gp330. Megalin is an endocytic receptor expressed on the apical surface of several epithelial cells that internalizes a variety of ligands including nutrients, hormones and their carrier proteins, signaling molecules, morphogens, and extracellular matrix proteins. Once internalized, these ligands are directed to the lysosomal degradation pathway or transported by transcytosis from one side of the cell to the opposite membrane. The availability of megalin at the cell surface is controlled by several regulatory mechanisms, including the phosphorylation of its cytoplasmic domain by GSK3, the proteolysis of the extracellular domain at the cell surface (shedding), the subsequent intramembrane proteolysis of the transmembrane domain by the gamma-secretase complex, and exosome secretion. Based on the important roles of its ligands and its tissue expression pattern, megalin has been recognized as an important component of many pathological conditions, including diabetic nephropathy, Lowe syndrome, Dent disease, Alzheimer's disease (AD) and gallstone disease. In addition, the expression of megalin and some of its ligands in the central and peripheral nervous system suggests a role for this receptor in neural regeneration processes. Despite its obvious importance, the regulation of megalin expression is poorly understood. In this review, we describe the functions of megalin and its association with certain pathological conditions as well as the current understanding of the mechanisms that underlie the control of megalin expression.

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Ultrastructural localization of megalin in the rat cochlear duct

Cited by 50 publications

References 32 publications

Soluble Megalin Is Accumulated in the Lumen of the Rat Endolymphatic Sac

Soluble Megalin Is Accumulated in the Lumen of the Rat Endolymphatic Sac

Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin

New Insights into the Roles of Megalin/LRP2 and the Regulation of its Functional Expression

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