N-Glycoform-dependent interactions of megalin with its ligands

Hirano, Masao; Totani, Kiichiro; Fukuda, Tomohiko; Gu, Jianguo; Suzuki, Akemi

doi:10.1016/j.bbagen.2016.10.015

Cited by 11 publications

(7 citation statements)

References 40 publications

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“…Since the comparison was based on the same gender (male), we realize that the significant expression difference of the glycan might be age-related, or disease related. It has been reported that glycans from 30 N-glycosylation sites of the large multiligand endocytic receptor megalin can modulate the ligand-binding capacity [84]. However, due to the small sample size of this study, additional research is required to elucidate conclusive evidence of proteinuria progression that associates with changed protein functions due to the glycan alternations.…”

Section: Comparison Between Proteinuria and Hypertension Groups And Control Groupmentioning

confidence: 88%

“…In addition, multiple studies have identified mutations in the BBM glycoproteins megalin and cubilin that are associated with kidney disease often manifested by proteinuria [73][74][75][76][77][78][79][80][81][82]. Further, ligand binding of both these multiligand receptors is impacted by their glycan state which would have a direct impact on levels of proteinuria [83][84][85][86]. Unfortunately, knowledge of BBM glycosylation, including cubilin and megalin, in disease states is limited as is an understanding of the changes to the glycan regulatory pathways with disease.…”

Section: Comparison Between Proteinuria and Hypertension Groups And Control Groupmentioning

confidence: 99%

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Changes in the Expression of Renal Brush Border Membrane N-Glycome in Model Rats with Chronic Kidney Diseases

Zhao

Yadav

et al. 2021

Biomolecules

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Chronic kidney disease (CKD) is defined by a reduced renal function i.e., glomerular filtration rate (GFR), and the presence of kidney damage is determined by measurement of proteinuria or albuminuria. Albuminuria increases with age and can result from glomerular and/or proximal tubule (PT) alterations. Brush-border membranes (BBMs) on PT cells play an important role in maintaining the stability of PT functions. The PT BBM, a highly dynamic, organized, specialized membrane, contains a variety of glycoproteins required for the functions of PT. Since protein glycosylation regulates many protein functions, the alteration of glycosylation due to the glycan changes has attracted more interests for a variety of disease studies recently. In this work, liquid chromatography-tandem mass spectrometry was utilized to analyze the abundances of permethylated glycans from rats under control to mild CKD, severe CKD, and diabetic conditions. The most significant differences were observed in sialylation level with the highest present in the severe CKD and diabetic groups. Moreover, high mannose N-glycans was enriched in the CKD BBMs. Characterization of all the BBM N-glycan changes supports that these changes are likely to impact the functional properties of the dynamic PT BBM. Further, these changes may lead to the potential discovery of glycan biomarkers for improved CKD diagnosis and new avenues for therapeutic treatments.

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Section: Comparison Between Proteinuria and Hypertension Groups And Control Groupmentioning

confidence: 88%

Section: Comparison Between Proteinuria and Hypertension Groups And Control Groupmentioning

confidence: 99%

Changes in the Expression of Renal Brush Border Membrane N-Glycome in Model Rats with Chronic Kidney Diseases

Zhao

Yadav

et al. 2021

Biomolecules

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“…The main product of the HBP, UDP-GlcNAc, is a precursor of UDP-GalNAc and CMP-Neu5Ac production (23), thus regulating the pattern of extracellular glycosylation. Recently, it was shown that the megalin glycophenotype modifies binding properties to different ligands, including albumin (24).…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAcylation reduces proximal tubule protein reabsorption and promotes proteinuria in spontaneously hypertensive rats

Silva-Aguiar

Bezerra

Lucena

et al. 2018

Journal of Biological Chemistry

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Hypertensive individuals are at greater risk for developing chronic kidney disease (CKD). Reducing proteinuria has been suggested as a possible therapeutic approach to treat CKD. However, the mechanisms underlying the development of proteinuria in hypertensive conditions are incompletely understood. Cardiac and vascular dysfunction is associated with changes in the -GlcNAcylation pathway in hypertensive models. We hypothesized that-GlcNAcylation is also involved in renal damage, especially development of proteinuria, associated with hypertension. Using the spontaneously hypertensive rat (SHR) model, we observed higher renal cortex -GlcNAcylation, glutamine-fructose aminotransferase (GFAT), and-GlcNAc transferase (OGT) protein expression, which positively correlated with proteinuria. Interestingly, this was observed in hypertensive, but not pre-hypertensive, rats. Pharmacological inhibition of GFAT decreased renal cortex -GlcNAcylation, proteinuria, and albuminuria in SHR. Using a proximal tubule cell line, we observed that increased-GlcNAcylation reduced megalin surface expression and albumin endocytosis , and the effects were correlated Moreover, megalin is -GlcNAcylated both and In conclusion, our results demonstrate a new mechanism involved in hypertension-associated proteinuria.

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“…The tissues would express tissue-specific megalin glycoforms. A recent study demonstrated that N-glycan modifications altered the ligand-binding activity of megalin (2). A subsequent study revealed that Oglycosylation on LDL receptor and related receptors enhanced the ligand interactions (30).…”

Section: H Conclusionmentioning

confidence: 99%

“…Megalin has been believed to capture those ligands nonspecifically. However, a recent study demonstrated that the glycosylation of megalin modified the ligand-binding activity (2). This article focuses on the function of endocytosis through megalin and on the effects of glycosylation on the ligand-binding activity of megalin.…”

Section: A Introductionmentioning

confidence: 99%

An Endocytic Receptor, Megalin-Ligand Interactions: Effects of Glycosylation

Hirano

2018

TIGG

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Incorporating substances from outside across plasma membranes is an essential process for cells. Receptor-mediated endocytosis plays important roles for uptake and subsequent degradation and processing of nutrients and vitamins. Megalin is a multiligand endocytic receptor that contributes to absorption of low molecular weight proteins on the cell surface. Megalin is a 600 kDa single-spanning transmembrane glycoprotein. It has a large extracellular domain in the N-terminus that contains four ligand-binding regions. Megalin binds with functionally and structurally distinct proteins (e.g., vitamin-binding proteins, carrier proteins and hormones) and chemical drugs (e.g., aminoglycosides) as ligands. Through the uptake of ligands, megalin mediates physiological functions in the body. Although megalin is highly glycosylated and the glycan structures have been analyzed using mass spectrometry, little has been known about the function of glycan on megalin. This article introduces the function of endocytosis mediated by megalin under physiological and pathological conditions and the effects of glycosylation of megalin on ligand-binding activity as function of glycans.

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N-Glycoform-dependent interactions of megalin with its ligands

Cited by 11 publications

References 40 publications

Changes in the Expression of Renal Brush Border Membrane N-Glycome in Model Rats with Chronic Kidney Diseases

Changes in the Expression of Renal Brush Border Membrane N-Glycome in Model Rats with Chronic Kidney Diseases

O-GlcNAcylation reduces proximal tubule protein reabsorption and promotes proteinuria in spontaneously hypertensive rats

An Endocytic Receptor, Megalin-Ligand Interactions: Effects of Glycosylation

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