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Evidence for an Essential Role of Megalin in Transepithelial Transport of Retinol

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Evidence for an Essential Role of Megalin in Transepithelial Transport of Retinol ARTICLES J Am Soc Nephrol 10: 685–695, 1999 Evidence for an Essential Role of Megalin in Transepithelial Transport of Retinol ERIK ILSØ CHRISTENSEN,* JAN ØIVIND MOSKAUG,‡ HENRIK VORUM,† CHRISTIAN JACOBSEN,† THOMAS E. GUNDERSEN,‡ ANDERS NYKJÆR,§ RUNE BLOMHOFF,‡ THOMAS E. WILLNOW§ and SØREN K. MOESTRUP† *Department of Cell Biology, Institute of Anatomy and †Department of Medical Biochemistry, University of Aarhus, Denmark; ‡Institute for Nutrition Research, University of Oslo, Norway; and §Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany. Abstract. Transepithelial transport of retinol is linked to reti- urinary excretion of RBP and retinol, demonstrating that glo- nol-binding protein (RBP), which is taken up and also synthe- merular filtered RBP-retinol of megalin-deficient mice escapes sized in a number of epithelia. By immunocytochemistry of uptake by proximal tubules. A direct megalin-mediated uptake human, rat, and mouse renal proximal tubules, a strong staining of purified RBP-retinol was indicated by surface plasmon in apical endocytic vacuoles, lysosomes, endoplasmic reticu- resonance analysis and uptake in immortalized rat yolk sac lum, Golgi, and basal vesicles was observed, in accordance cells. Uptake was partially inhibited by a polyclonal megalin with luminal endocytic uptake as well as a constitutive syn- antibody and the receptor-associated protein. The present data thesis and basal secretion of RBP. Analysis of mice with target show that the absence of RBP-binding megalin causes a sig- disruption of the gene for the major endocytic receptor of nificantly increased loss of RBP and retinol in the urine, proximal tubules, megalin, revealed no RBP in proximal tu- demonstrating a crucial role of megalin in vitamin A homeosta- bules of these mice. Western blotting and HPLC of the urine of sis. the megalin-deficient mice instead revealed a highly increased Retinol-binding protein (RBP1) is a 21-kD plasma protein and retinol subsequent to tubular uptake is being returned to the the main carrier of vitamin A (retinol) in plasma. Retinol is circulation again in complex with RBP. coupled to RBP in the liver and the complex is circulating in Because RBP is taken up in proximal tubules, and retinol plasma bound to transthyretin (TTR), previously named preal- stimulates the expression of megalin in a rat kidney proximal bumin, which to a certain extent prevents the RBP-retinol tubule cell line (10), we investigated if this highly expressed complex from being filtered in the glomeruli. However, 4 to receptor in proximal tubules might mediate uptake of RBP. 5% of the circulating RBP-retinol complex is not bound to Megalin, a 600-kD protein localized in the endocytic pathway TTR (1), and the kidney appears to be a very important organ of renal proximal tubules (11), belongs to the LDL receptor in the recycling of RBP-retinol, contributing about 50% of the family (12–14). The protein functions as an endocytic receptor total circulating pool of RBP-retinol as estimated in rat (2). In for a wide variety of substances, including lipoproteins (15– accordance with this, RBP has been intensively used clinically 18), albumin (19), and basic drugs (20) (reviewed in reference to determine proteinurias of tubular origin (3,4), further indi- (21)). In addition, megalin binds calcium and receptor-associ- cating that RBP is filtered to a major extent in the renal ated protein (RAP), a chaperone-like protein (22). Interest- glomeruli and taken up in proximal tubules as confirmed by ingly, megalin also functions as a receptor for endocytic uptake immunohistochemistry (5,6). The role of the kidney in retinol of the two vitamin carrier proteins, vitamin B12-carrier transco- homeostasis is also substantiated by the finding that acute renal balamin (23) and vitamin D-binding protein (A. Nykjær, D. failure induces significant elevations of serum retinol concen- Dragun, D. Walther, et al., Cell 1999, in press). These findings trations (7,8). Furthermore, RBP mRNA has been detected in demonstrate that megalin is fundamental for the retainment of rat kidney by in situ hybridization (9), and it is suggested that substances vital for the organism. The general importance of megalin is supported by the findings that knockout of the megalin gene in mice results in a high mortality and develop- Received September 23, 1998. Accepted October 5, 1998. mental abnormalities (24). Correspondence to Dr. Erik Ilsø Christensen, Department of Cell Biology, The present study was carried out to investigate the impor- Institute of Anatomy, University of Aarhus, DK-8000 Aarhus C, Denmark. Phone: (45) 89 42 30 57; Fax: (45) 86 19 86 64; E-mail: [email protected] tance of megalin for renal proximal tubular reabsorption and synthesis of RBP, which is suggested to control the transepi- 1046-6673/1004-0685$03.00/0 Journal of the American Society of Nephrology thelial transport of retinol. Using different approaches includ- Copyright © 1999 by the American Society of Nephrology ing immunocytochemistry and urine analyses of megalin-defi- 686 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 685–695, 1999 Figure 1. Immunohistochemical labeling of retinol-binding protein (RBP) in rat (A and B) and in human (C and D) renal cortex. (A) An intense labeling is seen in a cross-sectioned segment 1 (S1), including a granular and an apparent cytoplasmic labeling. One cell (arrow) shows a pronounced cytoplasmic labeling. In addition, these cells demonstrate labeling of several basal granules (arrowheads). A segment 2 proximal tubule (S2) shows only granular, probably lysosomal, labeling. (B) Granular labeling of segment 2 (S2) proximal tubules. One cell shows in addition intense cytoplasmic labeling (arrow). Distal tubule (DT) is unlabeled. (C) Section from human cortex demonstrates proximal tubules with intense granular labeling including basal granules (arrowheads) and varying cytoplasmic labeling. (D) Several interstitial fibroblast-like cells (arrows) exhibit an intense cytoplasmic labeling. Glomerulus (G) is unlabeled. Magnification: 31000 in A and C; 3750 in B and D. cient mice and normal control animals, ligand uptake studies in buffered with NH3, pH 10, as described (25). Purified RBP was then megalin-expressing cells, and ligand binding to purified mega- analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophore- lin, we now evidence a key function of megalin in this process. sis, together with known amounts of commercially available RBP (Sigma, St. Louis, MO). The gel was stained with Coomassie R-250, and the concentration of purified RBP was estimated visually by the Materials and Methods 2 Ligands and Antibodies intensity of the bands. RBP was stored frozen at 20°C. A rabbit polyclonal antihuman RBP antibody and a rabbit poly- RBP was purified from human plasma from Blodbanken, Ullevål clonal antihuman cathepsin D antibody were obtained from Dako sykehus, Oslo, Norway. Plasma was first dialyzed against 0.05 M (Dako A/S, Glostrup, Denmark), mouse monoclonal antihuman RBP NaH2PO4 containing 0.05 M NaCl, pH 7.5, to separate RBP-retinol was from Transduction Laboratories (Lexington, KY), and rat mono- from TTR at low ionic strength. The dialyzed plasma was then loaded clonal anti-mouse LAMP2 against lysosome-associated membrane onto a diethylaminoethyl-Sepharose Fast Flow column (Pharmacia, protein was a kind gift from Dr. Ira Mellman (Department of Cell Uppsala, Sweden) and eluted by a NaCl gradient, 0.05 to 0.6 M using Biology, Yale University School of Medicine, New Haven, CT). an fast protein liquid chromatography (Pharmacia). The fractions absorbing at 313 nm containing RBP were collected, pooled, and submitted to gel filtration in phosphate-buffered saline on a Superdex Preparation of Renal Tissue 200 preparative column using the fast protein liquid chromatography. Normal, uninvolved human renal tissue was obtained from resected The fractions absorbing at 313 nm were pooled and loaded onto a renal carcinoma kidneys and fixed in 8% paraformaldehyde in 0.1 M TTR (purchased from Scigen, Kent, United Kingdom)-coupled sodium cacodylate buffer, pH 7.2. Mouse megalin knockout and Sepharose at 140 mM NaCl and eluted at low ionic strength in water control kidneys were fixed by perfusion through the heart with 4% J Am Soc Nephrol 10: 685–695, 1999 Megalin-Mediated Endocytosis of RBP 687 Figure 2. Immunohistochemical labeling for RBP in wild-type mice (A and B) and in megalin-deficient mouse (C). (A) Intense granular labeling (arrowhead) of initial part of proximal tubule; arrow points to transition from Bowman’s capsule to proximal tubule epithelium. (B) Granular labeling of early proximal tubule (arrowhead); surrounding cross sections of proximal tubules are unlabeled. (C) Section from megalin-deficient mouse; no labeling is observed. Arrows indicate start of proximal tubule. (D) Section from wild-type mouse incubated without primary antibody shows no labeling. Arrow indicates start of proximal tubule. Magnification, 31000. paraformaldehyde in the same buffer, and rat kidneys were fixed by Ultracut E ultramicrotome. For immunolabeling, the sections were retrograde perfusion through the abdominal aorta with 1 or 4% para- incubated with primary polyclonal anti-RBP diluted 1:800 to 1:4000 formaldehyde. The tissue was trimmed into small blocks, further fixed or monoclonal anti-RBP (1 to 10 mg/ml) either at room temperature by immersion for1hin1%paraformaldehyde, infiltrated with 2.3 M for1horovernight at 4°C after preincubation in phosphate-buffered sucrose containing 2% paraformaldehyde for 30 min, and frozen in saline containing 0.05 M glycine and 0.1% nonfat dry milk or 1% liquid nitrogen. For some electron microscope immunocytochemical bovine serum albumin. For electron microscopic double labeling experiments, tissue treated and frozen as above was further freeze- experiments, sections from human kidneys were incubated with substituted in a Reichert AFS (Reichert, Vienna, Austria) as follows: monoclonal anti-RBP together with rabbit anti-cathepsin D, 1:5000 3 d in methanol containing 0.5% uranyl acetate at 280°C, washed in (cryosections) or 1:400 (HM20 embedded tissue).
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