Hypocalcemia and osteopathy in mice with kidney‐specific megalin gene defect

  title={Hypocalcemia and osteopathy in mice with kidney‐specific megalin gene defect},
  author={J R Leheste and Flemming Melsen and Maren Wellner and Pernille Jansen and Uwe Schlichting and I. C. E. Renner-M{\"u}ller and Troels Torp Andreassen and E. Wolf and Sebastian Bachmann and Anders Nykjaer and Thomas E. Willnow},
  journal={The FASEB Journal},
Megalin is an endocytic receptor highly expressed in the proximal tubules of the kidney. Recently, we demonstrated that this receptor is essential for the renal uptake and conversion of 25‐OH vitamin D3 to 1,25‐(OH)2 vitamin D3, a central step in vitamin D and bone metabolism. Unfortunately, the perinatal lethality of the conventional megalin knockout mouse model precluded the detailed analysis of the significance of megalin for calcium homeostasis and bone turnover in vivo. Here, we have… 

Megalin and Vitamin D Metabolism—Implications in Non-Renal Tissues and Kidney Disease

An overview of the current knowledge of megalin function in the context of vitamin D metabolism is provided, with an emphasis on extrarenal megal in, an area that clearly requires further investigation.

Role of Megalin, a Proximal Tubular Endocytic Receptor, in Calcium and Phosphate Homeostasis

  • A. SaitoN. IinoT. TakedaF. Gejyo
  • Biology, Medicine
    Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy
  • 2007
Megalin is expressed at the apical membranes of proximal tubule cells, acting as an endocytic receptor for a variety of ligands filtered by glomeruli, and decreased expression of megalin may be associated with the pathogenesis of hyperphosphaturia observed in patients with Dent's disease.

Megalin-mediated reuptake of retinol in the kidneys of mice is essential for vitamin A homeostasis.

It is demonstrated that urinary ROH excretion caused by megalin deficiency requires accelerated mobilization of hepatic VA stores to maintain normal plasma ROH levels, which suggests that megal in plays an essential role in systemic VA homeostasis.

Diagnosis and Management of Renal Osteodystrophy in Children

“Renal osteodystrophy” is the specific term used to describe the bone pathology that occurs as a complication of CKD and is therefore one aspect of the CKD-MBD.

Kidney-specific upregulation of vitamin D3 target genes in ClC-5 KO mice.

Mutations in ClC-5 cause Dent's disease, a disorder associated with low molecular weight proteinuria, hyperphosphaturia, and kidney stones. ClC-5 is a Cl(-)/H(+)-exchanger predominantly expressed in

Dysregulation of the Intrarenal Vitamin D Endocytic Pathway in a Nephropathy-Prone Mouse Model of Type 1 Diabetes

The studies show that intrarenal vitamin D handling is altered in the diabetic kidney, and they suggest that in T1D, urinary losses of VDBP may portend risk for intra Renal and extrarenal Vitamin D deficiencies.

Mouse model of proximal tubule endocytic dysfunction.

  • K. WeyerTina Storm R. Nielsen
  • Biology, Medicine
    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
  • 2011
The viable megalin/cubilin double-deficient mice now allow for detailed large-scale group analysis, and it is anticipated that the mice will be of great value as an animal model for proximal tubulopathies with disrupted endocytosis.

Selective Ablation of Megalin in the Retinal Pigment Epithelium Results in Megaophthalmos, Macromelanosome Formation and Severe Retina Degeneration

Postnatal loss of megalin in the RPE induces dramatic and rapid ocular growth and retinal degeneration compatible with the high myopia observed in Donnai-Barrow patients.

Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria.

Results show that megalin plays a pivotal role in the re absorption of small to large molecular size proteins and provides direct in vivo evidence that reabsorption of filtered proteins triggers events leading to tubule injury.



Megalin knockout mice as an animal model of low molecular weight proteinuria.

Expression profiling confirms the role of endocytic receptor megalin in renal vitamin D3 metabolism.

BACKGROUND The endocytic receptor megalin constitutes the major pathway for clearance of low-molecular weight plasma proteins from the glomerular filtrate into the renal proximal tubules.

Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein.

The role of DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of its bioavailability, activation, and end-organ responsiveness, which may have evolved to stabilize and maintain serum levels of Vitamin D in environments with variable vitamin D availability.

Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B(12).

It is shown that megalin is, in fact, essential for the normal renal reabsorption of TC-vitamin B(12) and for renal accumulation of this highly conserved vitamin.

Defective forebrain development in mice lacking gp330/megalin.

  • T. WillnowJ. Hilpert J. Herz
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1996
It is proposed that thegp330/megalin receptor is part of the maternal-fetal lipoprotein transport system and mediates the endocytic uptake of essential nutrients in the postgastrulation stage.

Extrarenal Expression of 25-Hydroxyvitamin D3-1α-Hydroxylase1

Further immunohistochemical and Western blot analyses are described that detail for the first time the extrarenal distribution of 1α-hydroxylase in both normal and diseased tissues.

Megalin Deficiency Offers Protection from Renal Aminoglycoside Accumulation*

It is demonstrated that the uptake of aminoglycosides into the kidney directly correlates with renal megalin activity and is completely eliminated in mice lacking the receptor, providing unequivocal evidence that megal in is the only major pathway responsible for renal aminglycoside accumulation.

Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3

It is reported that cubilin, a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid–carrier complexes on the cellular surface before megal in-mediated internalization of the cubil in-bound ligand.

Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase.

The data presented here confirm the presence of protein for 1 alpha-hydroxylase in several extrarenal tissues, such as skin, placenta, and lymph nodes, and the discrete patterns of staining in these tissues emphasizes a possible role for 1alpha-hydroxyylase as an intracrine modulator of vitamin D function in peripheral tissues.

Regulation of vitamin D-1alpha-hydroxylase in a human cortical collecting duct cell line.

The results highlight the capacity for synthesis of 1,25(OH)2D3 in cells from more distal areas of the nephron, and suggest a more localized role for 1,24-dihydroxyvitamin D3 production in the distal nephrons.