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Role of megalin and cubilin in the metabolism of vitamin d3Therapeutic Apheresis and Dialysis 15(Supplement 1):14–17doi: 10.1111/j.1744-9987.2011.00920.x 2011 The AuthorsTherapeutic Apheresis and Dialysis 2011 International Society for Apheresis Role of Megalin and Cubilin in the Metabolism of Ryohei Kaseda,1 Michihiro Hosojima,1 Hiroyoshi Sato,2 and Akihiko Saito2 1Division of Clinical Nephrology and Rheumatology and 2Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori, Chuo-ku, Niigata, Japan Abstract: Vitamin D deficiency is associated with various
tion of these receptors, which is commonly found in medical conditions including musculoskeletal disorders, patients with diabetic nephropathy, even at early stages, infection, metabolic diseases, and cardiovascular disease.
may explain why vitamin D deficiency is often complicated Megalin and cubilin, endocytic receptors in proximal in these patients. Therapeutic strategies to protect the func- tubule cells, are involved in the reabsorption of vitamin D tions of these receptors from injury could be used to binding protein from glomerular filtrates and the subse- prevent vitamin D deficiency and its related disorders.
quent intracellular conversion of 25-hydroxyvitamin D3 to Key Words: Chronic kidney disease, Cubilin, Diabetic
biologically active 1a,25-dihydroxyvitamin D3. Dysfunc- nephropathy, Megalin, Vitamin D deficiency.
Vitamin D is obtained exogenously through ders, infection, metabolic diseases, and cardiovascular dietary intake and is synthesized endogenously in disease (3). It develops early in the course of chronic the skin, where 7-dehydrocholesterol (pro-vitamin kidney disease (CKD), especially in diabetic nephr- D3) is converted to pre-vitamin D3 by UV radiation.
opathy. Treatment with the activated vitamin D ana- Pre-vitamin D3 then undergoes non-enzymatic logue calcitriol was shown to improve the survival isomerization to form cholecalciferol, or vitamin of patients suffering from this disorder (4), while D3. This enters the circulation and is carried by a recent meta-analysis of randomized controlled vitamin D binding protein (DBP) to the liver where studies of vitamin D supplementation in the general population suggests that it also decreases total mor- hydroxyvitamin D3 (25(OH)D3). Finally, 25(OH)D3 is again transported by DBP to the kidney, where In this review, we focus on the renal mechanism of it is hydroxylated by 1a-hydroxylase to 1a,25- vitamin D3 metabolism mediated by megalin and dihydroxyvitamin D3 (1,25(OH)2D3), which is the cubilin, as well as its disorder in CKD, particularly hormonally active form of vitamin D (1). It has recently been suggested by in vitro studies that con-version of 25(OH)D3 to 1,25(OH)2D3 may also occurin extra-renal cells, including keratinocytes, bone, pla- MEGALIN AND CUBILIN: ENDOCYTIC
centa, prostate, macrophages, T-lymphocytes, and RECEPTORS IN PROXIMAL TUBULE CELL
(PTC) APICAL MEMBRANES
Vitamin D deficiency is associated with various medical problems, including musculoskeletal disor- Megalin is a large (~600 kDa) glycoprotein member of the low-density lipoprotein receptorfamily that is primarily expressed in clathrin-coatedpits (6,7). Megalin plays a critical role in the reab- Received November 2010; revised November 2010.
Address correspondence and reprint requests to Professor sorption and metabolism of glomerular-filtered Akihiko Saito, Department of Applied Molecular Medicine, substances, including albumin and low molecular Niigata University Graduate School of Medical and Dental weight proteins. Megalin–ligand complexes are inter- Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata-shi, Niigata951-8510, Japan. Email: firstname.lastname@example.org nalized via clathrin-coated pits mediated by multiple Megalin and Cubulin in Vit D3 Metabolism intracellular adaptor proteins such as disabled 2(Dab2) and motor molecules to form endosomalvesicles (8). Acidification of the intravesicular lumendissociates the ligands from megalin and they are transported to lysosomes for degradation or storage,or translocated to the cytosol for further processing.
Megalin cooperates with cubilin, another endocytic Cubilin is a 460-kDa peripheral glycoprotein lacking transmembrane and intracellular segments, but is anchored to apical PTC membranes (7). It was originally identified as the receptor for the intrinsic are the cause of hereditary megaloblastic anemia 1and Imerslund–Gräsbeck syndrome, also known asselective vitamin B12 malabsorption with proteinuria Involvement of megalin and cubilin in vitamin D3 (10). Cubilin is also involved in the absorption of metabolism in proximal tubule cells: megalin and cubilin take up various protein ligands present in glomerular fil- vitamin D-binding protein (DBP) from glomerular filtrates. Fol-lowing degradation of DBP in lysosomes, 25-hydroxyvitamin D3 trates, including albumin and transferrin (7). It is bound by amnionless, a 50-kDa membrane protein, (1,25(OH)2D3) intracellularly and released into the circulation.
INVOLVEMENT OF MEGALIN AND CUBILIN
impaired in the early stages of diabetic nephropathy, IN VITAMIN D3 METABOLISM
since low molecular weight proteinuria is frequently A breakthrough in unveiling the link between Cellular expression of megalin was found to be endocytosis was the finding that megalin mediates downregulated by TGF-b (18). We also found the uptake of DBP from glomerular filtrates and that megalin expression in cultured PTCs is that the process is essentially involved in the conver- upregulated following treatment with insulin or high-concentration glucose. Conversely, it is down- active form (Fig. 1) (12,13). The relevance of DBP in regulated by angiotensin II (20). Furthermore, we the metabolism and activation of vitamin D was also demonstrated competitive cross-talk between angio- supported by results obtained using DBP knockout tensin II type 1 receptor- and insulin-mediated sig- mice (14). These findings challenged the previous naling pathways in the regulation of megalin free hormone hypothesis, which stated that the bio- expression in the cells (20). Angiotensin II may be a logical activity of a hormone is mediated by its major factor in suppressing megalin expression in unbound (free) form rather than its protein-bound the early stages of diabetic nephropathy since the forms in the plasma (15). Subsequently, cubilin was intrarenal renin–angiotensin system is activated in shown to be another endocytic receptor for DBP, with its genetic defects causing urinary loss of DBP The functions of cubilin may also be impaired in early diabetic nephropathy as urinary excretion of transferrin, an endocytic ligand of cubilin, is signifi- recent study, however, found that urinary DBP cantly increased in patients with this disease (22).
levels are not increased in cubilin knockout mice,suggesting that the mouse mechanism of DBP pro- VITAMIN D DEFICIENCY AND ITS LINK
WITH PTC ENDOCYTIC DYSFUNCTION
IMPAIRED ENDOCYTIC FUNCTIONS OF
PTCS IN DIABETIC NEPHROPATHY
The type 2 diabetes animal model, Zucker fatty rats, shows reduced 25(OH)D3 and 1,25(OH)2D3 Decreased megalin expression in PTCs has been serum levels, which are associated with increased observed in the early diabetic stages of experimental urinary excretion of these vitamin D metabolites and animals (18). Megalin function is also believed to be DBP and reduced renal expression of megalin and 2011 The AuthorsTherapeutic Apheresis and Dialysis 2011 International Society for Apheresis Ther Apher Dial, Vol. 15, Supplement 1, 2011 Dab2 (23). It was also found that increased urinary 2. Lehmann B, Meurer M. Vitamin D metabolism. Dermatol Ther excretion of DBP is associated with vitamin D defi- 3. Adams JS, Hewison M. Update in vitamin D. J Clin Endo- ciency in patients with type 1 diabetes (24). Interven- crinol Metab 2010;95:471–8.
tional studies should therefore be conducted to 4. Shoben AB, Rudser KD, de Boer IH, Young B, Kestenbaum investigate whether vitamin D deficiency is pre- B. Association of oral calcitriol with improved survival in non-dialyzed CKD. J Am Soc Nephrol 2008;19:1613–19.
vented by maintaining the function of megalin and 5. Autier P, Gandini S. Vitamin D supplementation and total cubilin in patients with CKD, especially those with mortality: a meta-analysis of randomized controlled trials.
Arch Intern Med 2007;167:1730–7.
6. Saito A, Pietromonaco S, Loo AK, Farquhar MG. Complete cloning and sequencing of rat gp330/“megalin,” a distinctivemember of the low density lipoprotein receptor gene family.
EFFECTS OF VITAMIN D RECEPTOR
Proc Natl Acad Sci USA 1994;91:9725–9.
ACTIVATION ON THE REDUCTION
7. Saito A, Sato H, Iino N, Takeda T. Molecular mechanisms of OF ALBUMINURIA IN
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8. Hosaka K, Takeda T, Iino N et al. Megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Recently, a randomized controlled trial showed Disabled-2 in proximal tubule cells. Kidney Int 2009;75:1308– that the daily administration of 2 mg paricalcitol, an 9. Seetharam B, Levine JS, Ramasamy M, Alpers DH. Purifica- analogue of the active form of vitamin D3, to renin- tion, properties, and immunochemical localization of a recep- angiotensin-aldosterone inhibition lowered residual tor for intrinsic factor-cobalamin complex in the rat kidney. J albuminuria in patients with diabetic nephropathy. A 10. Aminoff M, Carter JE, Chadwick RB et al. Mutations in lower dose (1 mg/day) of the drug produced no favor- CUBN, encoding the intrinsic factor-vitamin B12 receptor, able effects (VITAL study) (25). The mechanisms of cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet paricalcitol action on the kidney remain unknown, so 11. Fyfe JC, Madsen M, Hojrup P et al. The functional cobalamin it would be of interest to investigate whether it is (vitamin B12)-intrinsic factor receptor is a novel complex of taken up via the megalin–cubilin system and if it acts cubilin and amnionless. Blood 2004;103:1573–9.
on the PTC vitamin D receptor. High-dose paricalci- 12. Nykjaer A, Dragun D, Walther D et al. An endocytic pathway essential for renal uptake and activation of the steroid tol may have been needed to generate such a benefi- 25-(OH) vitamin D3. Cell 1999;96:507–15.
cial effect in patients with diabetic nephropathy 13. Saito A, Iino N, Takeda T, Gejyo F. Role of megalin, because of the reduced renal functions of megalin a proximal tubular endocytic receptor, in calcium andphosphate homeostasis. Ther Apher Dial 2007;11(Suppl 1): 14. Safadi FF, Thornton P, Magiera H et al. Osteopathy and resis- tance to vitamin D toxicity in mice null for vitamin D binding CONCLUSIONS
protein. J Clin Invest 1999;103:239–51.
15. Mendel CM. The free hormone hypothesis: a physiologically The endocytic PTC receptors megalin and cubilin based mathematical model. Endocr Rev 1989;10:232–74.
are involved in the metabolism of vitamin D by reab- 16. Nykjaer A, Fyfe JC, Kozyraki R et al. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) sorbing DBP from glomerular filtrates. Dysfunction of vitamin D(3). Proc Natl Acad Sci USA 2001;98:13895– these receptors is likely to be associated with the development of vitamin D deficiency in patients with 17. Amsellem S, Gburek J, Hamard G et al. Cubilin is essential for albumin reabsorption in the renal proximal tubule. J Am Soc CKD, in particular those with diabetic nephropathy.
Therapeutic strategies to protect the functions of 18. Russo LM, del Re E, Brown D, Lin HY. Evidence for a role of these receptors from injury could be investigated to transforming growth factor (TGF)-beta1 in the induction ofpostglomerular albuminuria in diabetic nephropathy: amelio- prevent vitamin D deficiency and its related disorders.
ration by soluble TGF-beta type II receptor. Diabetes 2007;56:380–8.
Conflict of interests: The authors have no conflict of
19. Hong CY, Hughes K, Chia KS, Ng V, Ling SL. Urinary alpha1-microglobulin as a marker of nephropathy in type 2 diabetic Asian subjects in Singapore. Diabetes Care 2003;26:338–42.
Acknowledgments: This work was supported by a
20. Hosojima M, Sato H, Yamamoto K et al. Regulation of Grant-in-Aid for Scientific Research from the Ministry of megalin expression in cultured proximal tubule cells by angio- Education, Science, and Culture of Japan (21591023).
tensin II type 1A receptor- and insulin-mediated signalingcross talk. Endocrinology 2009;150:871–8.
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