Regulation of gp330/megalin expression by vitamins A and D

W, Liu; Yu, Wenli; Carling, Tobias; Juhlin, Claes; Rastad, Jonas; Ridefelt, Peter; Åkerström, Göran; Hellman, Per

doi:10.1046/j.1365-2362.1998.00253.x

Cited by 87 publications

(63 citation statements)

References 30 publications

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“…Since the apelin receptor APJ is not detectable in this renal structure, the effect of APLN-13 may be indirect. Megalin mRNA expression in the proximal tubules is stimulated by various factors, including vitamin A and vitamin D (33). The mechanism by which Apelin regulates megalin expression remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Apelin retards the progression of diabetic nephropathy

Day

Cavaglieri

Féliers

2013

American Journal of Physiology-Renal Physiology

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Day RT, Cavaglieri RC, Feliers D. Apelin retards the progression of diabetic nephropathy. Am J Physiol Renal Physiol 304: F788-F800, 2013. First published January 9, 2012; doi:10.1152/ajprenal.00306.2012.-Apelin and its receptor APJ have pleiotropic effects in mice and humans and play a protective role in cardiovascular diseases at least partially by inhibiting oxidative stress. Our objective was to study the effect of apelin on the progression of kidney disease in mice with established type 1 diabetes. Ove26 mice with type 1 diabetes received daily subcutaneous injections of apelin for 2 or 14 wk. APJ localizes in the glomeruli and blood vessels of kidneys. Renal APJ expression was reduced in diabetic mice but increased after treatment with apelin. Apelin treatment did not affect glycemia, body weight, or blood pressure in diabetic mice. Whole kidney and glomerular hypertrophy, as well as renal inflammation, including monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression, NF-B activation, and monocyte infiltration, was inhibited after short and long treatment with apelin. Apelin administration significantly reduced albuminuria at 6 mo. Short treatment with apelin was sufficient to reverse the downregulation of the antioxidant enzyme catalase. Expression of angiotensin II and angiotensin type 1 receptor (AT1) in kidneys from diabetic mice treated was not affected by apelin. These findings show for the first time that apelin exerts a protective effect on the diabetic kidney. Short administration is sufficient to reduce kidney and glomerular hypertrophy as well as renal inflammation, but prolonged treatment is required to improve albuminuria. This effect was independent of the activation of the renin angiotensin system but correlated with upregulation of the antioxidant catalase. Apelin may represent a novel tool to treat diabetic nephropathy. diabetes; nephropathy; apelin; inflammation DIABETES IS THE MOST COMMON cause of end-stage renal disease (1) and nephropathy affects 20% of patients with type 1 diabetes (60). Early manifestations of diabetic nephropathy include the development of hyperfiltration and hypertrophy, thickening of the glomerular basement membrane, and mesangial matrix expansion. This is followed by increased urinary albumin excretion, glomerulosclerosis, tubulo-interstitial fibrosis, and end-stage renal failure. Current treatment strategies, including tight glycemic control (7a) and inhibition of the renin angiotensin system (32), slow down progression of diabetic nephropathy but do not reverse the course of diabetic nephropathy. The renin-angiotensin-aldosterone system contributes importantly to the pathogenesis of diabetic nephropathy; thus the role played by recently identified novel modulators of angiotensin actions such as apelin would be of significant interest. However, little is known about the effect of apelin in the kidney.Oxidative stress has been shown to play an important role in the development of diabetic nephropathy (4,22). Oxidative stress is due to...

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Section: Discussionmentioning

confidence: 99%

Apelin retards the progression of diabetic nephropathy

Day

Cavaglieri

Féliers

2013

American Journal of Physiology-Renal Physiology

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“…Because it is known that megalin expression is positively regulated by vitamin D through VDR (55) and recently it was demonstrated that LCA is a ligand for VDR (41), we decided to explore the possibility that megalin expression was regulated, in vitro and in vivo, by BAs as LCA. In vitro, megalin expression was greatly decreased at LCA concentrations that activate its known mediator FXR (Ͼ25 M) and was slightly increased or not changed by lower concentrations of LCA that activate VDR (5-10 M) (41).…”

Section: Discussionmentioning

confidence: 99%

“…The fact that megalin expression is regulated by retinoic acid and vitamin D suggests the involvement of the transcription factors vitamin D receptor (VDR) and retinoid X receptor (RXR) in its regulation (55). Because the hydrophobic secondary BA LCA binds with high affinity to VDR (41), it is also possible that the expression of megalin could be regulated by BAs.…”

Section: Regulation Of Megalin Protein Expression By Bas In Vitromentioning

confidence: 99%

Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids

Erranz

Miquel

Argraves

et al. 2004

Journal of Lipid Research

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Cholesterol crystal formation in the gallbladder is a key step in gallstone pathogenesis. Gallbladder epithelial cells might prevent luminal gallstone formation through a poorly understood cholesterol absorption process. Genetic studies in mice have highlighted potential gallstone susceptibility alleles, Lith genes, which include the gene for megalin. Megalin, in conjunction with the large peripheral membrane protein cubilin, mediates the endocytosis of numerous ligands, including HDL/apolipoprotein A-I (apoA-I). Although the bile contains apoA-I and several cholesterol-binding megalin ligands, the expression of megalin and cubilin in the gallbladder has not been investigated. Here, we show that both proteins are expressed by human and mouse gallbladder epithelia. In vitro studies using a megalin-expressing cell line showed that lithocholic acid strongly inhibits and cholic and chenodeoxycholic acids increase megalin expression. The effects of bile acids (BAs) were also demonstrated in vivo, analyzing gallbladder levels of megalin and cubilin from mice fed with different BAs. The BA effects could be mediated by the farnesoid X receptor, expressed in the gallbladder. Megalin protein was also strongly increased after feeding a lithogenic diet. These results indicate a physiological role for megalin and cubilin in the gallbladder and provide support for a role for megalin in gallstone pathogenesis.

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“…At the transcriptional level, megalin mRNA expression is augmented by retinoic acid (vitamin A) and vitamin D treatment in cells from different origins and species (Liu et al, 1998). Both vitamins A and D carried by their specifi c vitamin binding proteins, RBP and DBP, are endocytosed by megalin.…”

Section: Regulation Of Megalin Mrna and Protein Expressionmentioning

confidence: 99%

“…In breast cancer cells, the expression of megalin, its coreceptor cubilin and the adaptor protein Dab2 are induced by retinoic acid (Chlon et al, 2008). The differentiation state of cells, such as rat PT cells and F9 embryonal carcinoma cells, also positively regulates the expression of megalin (Liu et al, 1998). For example, the differentiation of F9 cells with retinoic acid and cAMP induces the expression of megalin protein and of the RAP (Czekay et al, 1995).…”

Section: Regulation Of Megalin Mrna and Protein Expressionmentioning

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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Regulation of gp330/megalin expression by vitamins A and D

Abstract: The results indicate a correlation between exposure to retinoic acid or vitamin D or induction of cell differentiation (by retinoic acid/cAMP in F9 cells or inhibition of SV40 transcription in IRPTCs) and an increase in gp330/megalin protein and mRNA expression.

Cited by 87 publications

References 30 publications

Apelin retards the progression of diabetic nephropathy

Apelin retards the progression of diabetic nephropathy

Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids

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

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