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Megalin vitamin d

Christine C Akoh, Eva K Pressman, Corrie M Whisner, Carrie Thomas, Chang Cao, Tera Kent, Elizabeth Cooper, Kimberly O O'Brien
Vitamin D is thought to modulate innate immune responses, and recent studies have highlighted the autocrine and paracrine functions of vitamin D in the placenta. Our objective was to determine the relationship between maternal vitamin D status and placental antimicrobial peptide (AMP) expression in a group of racially and ethnically diverse pregnant adolescents. In this study, 158 pregnant adolescents were recruited from the Rochester Adolescent Maternity Program (RAMP) in Rochester, NY. Maternal serum concentrations of the vitamin D biomarkers, 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D), were measured at mid-gestation (∼26 weeks) and at delivery...
June 2017: Journal of Reproductive Immunology
May A Beydoun, Salman M Tajuddin, Greg A Dore, Jose-Atilio Canas, Hind A Beydoun, Michele K Evans, Alan B Zonderman
Background: The link between longitudinal cognitive change and polymorphisms in the vitamin D receptor (VDR) and MEGALIN [or LDL receptor-related protein 2 (LRP2)] genes remains unclear, particularly among African-American (AA) adults.Objectives: We aimed to evaluate associations of single nucleotide polymorphisms (SNPs) for VDR [rs11568820 (Cdx-2:T/C), rs1544410 (BsmI:G/A), rs7975232 (ApaI:A/C), rs731236 (TaqI:G/A)] and LRP2 [rs3755166:G/A,rs2075252:C/T, rs2228171:C/T] genes with longitudinal cognitive performance change in various domains of cognition...
June 2017: Journal of Nutrition
Tara C Brennan-Speranza, David Mor, Rebecca S Mason, John R Bartlett, Gustavo Duque, Itamar Levinger, Pazit Levinger
Muscle function is often impaired in patients with knee osteoarthritis (OA), with reduced strength and increased pain. The role of vitamin D and the vitamin D-endocrine pathway in muscle health has recently been placed in the spotlight, with various groups reporting positive effects on muscle development, function and health. Recently, it has been shown that uptake into muscle of the specialized vitamin D binding protein (DBP) is dependent on the endocytic receptor, megalin. Here we analyse circulating vitamin D, and muscle DBP, megalin and the cognate vitamin D receptor (VDR) in patients with knee OA and compare them to asymptomatic controls...
February 1, 2017: Journal of Steroid Biochemistry and Molecular Biology
Makoto Hirano, Kiichiro Totani, Tomohiko Fukuda, Jianguo Gu, Akemi Suzuki
BACKGROUND: Megalin is a 600-kDa single-spanning transmembrane glycoprotein and functions as an endocytic receptor, distributed not only in the kidney but also in other tissues. Structurally and functionally distinct ligands for megalin have been identified. Megalin has 30 potential N-glycosylation sites in its extracellular domain. We found that megalin interacts with its ligands in a glycoform-dependent manner. METHODS: Distribution of megalin and glycans was histochemically analyzed in mouse kidneys...
January 2017: Biochimica et Biophysica Acta
B Ruggiero, B L Padwa, K M Christoph, S Zhou, J Glowacki
Vitamin D is crucial for mineral homeostasis and contributes to bone metabolism by inducing osteoblast differentiation of marrow stromal cells (MSCs). We recently reported that MSCs from adults demonstrate 1α-hydroxylase activity in vitro and express vitamin D-related genes; this raises a possible autocrine/paracrine role for D activation in pre-osteoblasts. In this studies, we tested the hypotheses that pediatric MSCs have 1α-hydroxylase activity and express vitamin D-related genes. With IRB approval, we isolated MSCs from discarded excess iliac marrow graft from 6 male and 6 female subjects (age 8-12 years) undergoing alveolar cleft repair...
November 2016: Journal of Steroid Biochemistry and Molecular Biology
Xiaowen Lu, Rodolfo A Elizondo, Rikke Nielsen, Erik I Christensen, Jun Yang, Bruce D Hammock, Mitchell A Watsky
PURPOSE: To determine the source(s) of vitamin D in tear fluid and examine the expression of the endocytic proteins and putative vitamin D transporters megalin and cubilin in lacrimal and Harderian glands. METHODS: Wild-type, heterozygous, and vitamin D receptor (VDR) knockout C57BL/6 mice were used, with a subset of knockout mice fed a replenishment diet for some studies. Mouse lacrimal and Harderian glands from each group were used to measure megalin and cubilin by RT-PCR, Western blot, and immunohistochemistry...
September 2015: Investigative Ophthalmology & Visual Science
Russell W Chesney
Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia, glycosuria, aminoaciduria, and renal tubular acidosis. This indicates that vitamin D and its metabolites influence proximal tubule function. Filtered 25(OH)D bound to vitamin D binding protein (DBP) is endocytosed by megalin-cubilin in the apical membrane. Intracellular 25(OH)D is metabolized to 1,25(OH)2D or calcitroic acid by 1-α-hydroxylase or 24-hydroxylase in tubule cell mitochondria...
January 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
May A Beydoun, Toshiko Tanaka, Hind A Beydoun, Eric L Ding, Luigi Ferrucci, Alan B Zonderman
We examined longitudinal associations of vitamin D receptor (VDR) and megalin (LRP2; LDL receptor-related protein-2) gene polymorphisms with central adiposity. We used data from the Baltimore Longitudinal Study of Aging (BLSA), an ongoing prospective open cohort study. Study participants consisted of non-Hispanic white adults residing in Baltimore city, with one or more visits at age ≥50 years, and complete data (n 609-617). Repeated assessments on waist circumference (WC) and waist:hip ratio (WHR) were available...
2013: Journal of Nutritional Science
Gar Yee Koh, Elizabeth M Whitley, Kirsten Mancosky, Yi Ting Loo, Kelly Grapentine, Emily Bowers, Kevin L Schalinske, Matthew J Rowling
BACKGROUND: Type 2 diabetes (T2D) is the leading cause of nephropathy in the United States. Renal complications of T2D include proteinuria and suboptimal serum 25-hydroxycholecalciferol (25D) concentrations. 25D is the major circulating form of vitamin D and renal reabsorption of the 25D-vitamin D-binding protein (DBP) complex via megalin-mediated endocytosis is believed to determine whether 25D can be activated to 1,25-dihydroxycholecalciferol (1,25D) or returned to circulation. We previously demonstrated that excessive urinary excretion of 25D-DBP and albuminuria occurred in rats with type 1 diabetes (T1D) and T2D...
November 2014: Journal of Nutrition
Venkatesan Raghavan, Youssef Rbaibi, Núria M Pastor-Soler, Marcelo D Carattino, Ora A Weisz
The kidney has an extraordinary ability to maintain stable fractional solute and fluid reabsorption over a wide range of glomerular filtration rates (GFRs). Internalization of filtered low molecular weight proteins, vitamins, hormones, and other small molecules is mediated by the proximal tubule (PT) multiligand receptors megalin and cubilin. Changes in GFR and the accompanying fluid shear stress (FSS) modulate acute changes in PT ion transport thought to be mediated by microvillar bending. We found that FSS also affects apical endocytosis in PT cells...
June 10, 2014: Proceedings of the National Academy of Sciences of the United States of America
Jawaher A Alsalem, Deepali Patel, Radhika Susarla, Miguel Coca-Prados, Rosemary Bland, Elizabeth A Walker, Saaeha Rauz, Graham R Wallace
PURPOSE: Vitamin D3 is a secosteroid mainly synthesized from the conversion of the skin precursor 7-dehydrocholesterol (7DHC) to vitamin D3 by ultraviolet (UV) B sunlight. Extrarenal synthesis of vitamin D3 has been reported in many tissues and cells, including barrier sites. This study characterizes the expression of components of vitamin D3 signaling in human ocular barrier cells. METHODS: Primary human scleral fibroblasts (HSF), human corneal endothelial (HCEC-12), nonpigmented ciliary body epithelial (ODM-2), and adult retinal pigment epithelial (ARPE-19) cell lines were analyzed for the expression of vitamin D receptor (VDR), the vitamin D3 activating enzymes 1α-hydroxylase (CYP27B1), 25-hydroxylases (CYP27A1 and CYP2R1), the vitamin D3 inactivating enzyme 24-hydroxylase (CYP24A1), and the endocytic receptors cubilin and megalin using a combination of RT-PCR, immunocytochemistry, and enzyme immunoassay (EIA)...
April 7, 2014: Investigative Ophthalmology & Visual Science
Myriam Abboud, Clare Gordon-Thomson, Andrew J Hoy, Seher Balaban, Mark S Rybchyn, Louise Cole, Yingying Su, Tara C Brennan-Speranza, David R Fraser, Rebecca S Mason
Vitamin D status, measured as serum 25-hydroxyvitamin D (25OHD) concentration, is determined by rates of input and of degradation. The half-life of 25OHD is surprisingly long for a steroid and much longer than its blood transporter, vitamin D binding protein. There is some evidence to suggest that vitamin D itself is stored in fat, whereas 25OHD concentrations are usually related to muscle-related parameters such as lean body mass and exercise. Both muscle and fat cells come from the mesenchymal cell lineage...
October 2014: Journal of Steroid Biochemistry and Molecular Biology
Shantel B Ternes, Matthew J Rowling
Megalin and disabled-2 (Dab2) are essential for uptake of the 25-hydroxycholecalciferol (25D3)-vitamin D binding protein (DBP) complex in tissues. In the kidney, this mechanism regulates serum 25D3 levels and production of 1,25-dihydroxycholecalciferol (1,25D3) by CYP27B1 for systemic use. Previously, we showed that mammary epithelial cells expressing CYP27B1 express megalin and Dab2 and internalize DBP by endocytosis, indicating 25D3 was accessible for conversion to 1,25D3 in extra-renal tissues. Moreover, induction of megalin and Dab2 (protein and mRNA abundance) by all-trans-retinoic acid (RA) enhanced DBP uptake...
2013: Nutrition and Cancer
Laura N Anderson, Michelle Cotterchio, Julia A Knight, Ayelet Borgida, Steven Gallinger, Sean P Cleary
Recent studies of 25-hydroxyvitamin D (25(OH)D) levels and pancreas cancer have suggested a potential role of the vitamin D pathway in the etiology of this fatal disease. Variants in vitamin-D related genes are known to affect 25(OH)D levels and function and it is unknown if these variants may influence pancreatic cancer risk. The association between 87 single nucleotide polymorphisms (SNPs) in 11 genes was evaluated within the Ontario Pancreas Cancer Study, a population-based case-control study. Pancreatic cancer cases with pathology confirmed adenocarcinoma were identified from the Ontario Cancer Registry (n = 628) and controls were identified through random digit dialing (n = 1193)...
2013: PloS One
M Abboud, D A Puglisi, B N Davies, M Rybchyn, N P Whitehead, K E Brock, L Cole, C Gordon-Thomson, D R Fraser, R S Mason
Little is known about the mechanism for the prolonged residence time of 25-hydroxyvitamin D (25OHD) in blood. Several lines of evidence led us to propose that skeletal muscle could function as the site of an extravascular pool of 25OHD. In vitro studies investigated the capacity of differentiated C2 murine muscle cells to take up and release 25OHD, in comparison with other cell types and the involvement of the membrane protein megalin in these mechanisms. When C2 cells are differentiated into myotubes, the time-dependent uptake of labeled 25OHD is 2-3 times higher than in undifferentiated myoblasts or nonmuscle osteoblastic MG63 cells (P < ...
September 2013: Endocrinology
Anne L Smazal, Nicholas C Borcherding, Alysse S Anderegg, Kevin L Schalinske, Elizabeth M Whitley, Matthew J Rowling
Diabetes is a rapidly growing epidemic affecting millions of Americans and has been implicated in a number of devastating secondary complications. We previously demonstrated that type 2 diabetic rats exhibit vitamin D deficiency due to aberrant megalin-mediated endocytosis and excessive urinary excretion of 25-hydroxycholecalciferol (25D3) and vitamin D-binding protein (DBP). Here, we examined whether a model of type 1 diabetes [T1D; streptozotocin (STZ)-treated Sprague-Dawley rats] would similarly excrete abnormally high concentrations of 25D3 and DBP due to renal damage and compromised expression of megalin and its endocytic partner, disabled-2 (Dab2)...
July 2013: Journal of Nutrition
Erik I Christensen, Rikke Nielsen, Henrik Birn
Cubilin is a large endocytic receptor serving such diverse functions as the intestinal absorption of the intrinsic factor-B(12) complex and the renal proximal tubule reabsorption of filtered proteins including albumin, transferrin, vitamin D-binding protein and other important plasma carriers. Cubilin is a structurally unique, peripheral membrane protein, which depends on the membrane protein amnionless (AMN) for correct apical translocation. In addition, AMN appears important for efficient internalization of intrinsic factor-B(12) in the intestine, whereas in the proximal tubule cubilin interacts with another endocytic receptor, megalin, for effective reabsorption...
February 2013: Nephrology, Dialysis, Transplantation
Gregory P Levin, Cassianne Robinson-Cohen, Ian H de Boer, Denise K Houston, Kurt Lohman, Yongmei Liu, Stephen B Kritchevsky, Jane A Cauley, Toshiko Tanaka, Luigi Ferrucci, Stefania Bandinelli, Kushang V Patel, Emil Hagström, Karl Michaëlsson, Håkan Melhus, Thomas Wang, Myles Wolf, Bruce M Psaty, David Siscovick, Bryan Kestenbaum
CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes...
November 14, 2012: JAMA: the Journal of the American Medical Association
Tina Storm, Lisbeth Tranebjærg, Carina Frykholm, Henrik Birn, Pierre J Verroust, Tryggve Nevéus, Birgitta Sundelin, Jens Michael Hertz, Gerd Holmström, Katharina Ericson, Erik I Christensen, Rikke Nielsen
BACKGROUND: The reabsorption of filtered plasma proteins, hormones and vitamins by the renal proximal tubules is vital for body homeostasis. Studies of megalin-deficient mice suggest that the large multi-ligand endocytic receptor megalin plays an essential role in this process. In humans, dysfunctional megalin causes the extremely rare Donnai-Barrow/Facio-Oculo-Acustico-Renal (DB/FOAR) syndrome characterized by a characteristic and multifaceted phenotype including low-molecular-weight proteinuria...
March 2013: Nephrology, Dialysis, Transplantation
Masafumi Fukagawa, Hirotaka Komaba, Takayuki Hamano
Vitamin D not only plays important roles in mineral metabolism, but also affects the risk of mortality and cardiovascular events. Since the kidney is the main organ that produces 1,25-dihydroxyvitamin D, active vitamin D sterols are widely used in patients with chronic kidney disease (CKD), especially those with secondary hyperparathyroidism. CKD patients also have higher risk of vitamin D deficiency, due to urinary loss associated with proteinuria and possible down-regulation of megalin in the proximal tubular cells...
2012: Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum
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