Megalin Antagonizes Activation of the Parathyroid Hormone Receptor

Hilpert, Jan; Nykjaer, Anders; Jacobsen, Christian; Wallukat, Gerd; Nielsen, Rikke; Moestrup, Søren K.; Haller, Hermann; Luft, Friedrich C.; Christensen, Erik I.; Willnow, Thomas E.

doi:10.1074/jbc.274.9.5620

Cited by 110 publications

(52 citation statements)

References 38 publications

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“…Approximately 40 substances, including various glycoproteins, apolipoproteins, vitamin carrier proteins, and hormones have been reported as ligands of megalin [4]. Megalin localizes in the endocytic pathway of tubular epithelium and transports the ligands to the lysosomes [8,12,13,18,21,24,27,28,33]. Although our present findings indicated species-specific differences in tubular lysosome systems in rodent kidneys, the functional meanings of these differences remained unclear.…”

Section: Discussioncontrasting

confidence: 46%

Rodent Renal Structure Differs among Species

et al. 2006

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ABSTRACT. In the present study, we histologically and morphometrically investigated species differences in renal structure using laboratory rodents (mice, gerbils, hamsters, rats, and guinea pigs). Morphometric parameters were as follows, 1) diameter of the cortical renal corpuscles, 2) diameter of the juxtamedullary renal corpuscles, 3) percentage of the renal corpuscles with a cuboidal parietal layer, 4) number of nuclei in proximal convoluted tubules (PCTs) per unit area of cortex, 5) semi-quantitative score of the periodic acid-Schiff (PAS) -positive granules in PCTs, and 6) semi-quantitative score of the PAS-positive granules in proximal straight tubules (PSTs). Significant species differences were detected for each parameter, and particularly severe differences were observed in the PAS-positive granules of PCTs and PSTs. Granular scores varied among species and sexes. Vacuolar structures that did not stain with PAS or hematoxylin-eosin were observed in the renal proximal tubules. The appearance and localization of these vacuolar structures differed remarkably between species and sexes. KEY WORDS: morphology, morphometry, rodent kidney, sex difference, species specific difference.J. Vet. Med. Sci. 68(5): 439-445, 2006 A thorough understanding of the complex structures of the mammalian kidney provides a basis for comprehending the multitude of functional characteristics of this organ in both healthy and diseased states. The structure of this organ is closely related to its functions including production of urine, regulation of osmolarity, pH, body fluid composition and blood pressure, and metabolism of various substances. Many reports have addressed species-specific differences in mammalian kidneys [1,3,9,10,14,20,25]. In laboratory rodents, glomerular filtration rate (GFR) [10], activities of some dehydrogenases in the macula densa [14], and maxim urine-concentrating capacity [20] were found to differ among species. However, because of a lack of comparative studies, morphological differences in renal structure remain unclear. In the present study, to clarify species differences in renal structure of laboratory rodents, we comparatively investigated the kidneys of mice, gerbils, hamsters, rats, and guinea pigs using a morphometric approach. MATERIALS AND METHODS Animals:Male and female DBA/2CrSlc mice (n=5/each sex), MON/JmsGbsSlc gerbils (n=3/each sex), Slc:Syrian hamsters (n=3/each sex), F344/NSlc rats (n=4/each sex) and Slc:Hartley guinea pigs (n=3/each sex) were used in the present study. All animals were housed in an open system room with a one-way airflow system (temperature 22 ± 1°C; humidity 55 ± 10%; light period 07:00 to 19:00; ventilation 12 cycles/hr), and were given an autoclaved commercial diet (CE-2; Japan CLEA Inc., Tokyo, Japan) and tap water ad libitum. The present study was performed in accordance with the Guidelines for Animal Experimentation of Kagoshima University, Japan. All animals were sacrificed at 90 days of age by exanguination of the carotid arteries under anesthesia using a m...

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Section: Discussioncontrasting

confidence: 46%

Rodent Renal Structure Differs among Species

et al. 2006

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“…This event generates a series of N-truncated "CPTH" fragments (the corresponding N-terminal segments are destroyed in situ) that reenter the circulation and are cleared mainly by glomerular filtration, an important route for PTH clearance as well (4 ). Chemical analysis of PTH fragments isolated from rat blood after administration of radiolabeled bovine PTH established that hepatic metabolism yields a family of CPTH fragments with NH 2 termini ranging between residues 34 and 43, although the methods used likely would not have detected substantially larger CPTH fragments (5 ).…”

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confidence: 99%

Circulating Forms of Parathyroid Hormone: Peeling Back the Onion

Bringhurst

2003

Clinical Chemistry

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“…19 It is found in the clathrin-coated pits of PTC; it internalizes ligands into endocytotic compartments, and it is then recycled to the cell surface. 31,33 Ligands that are endocytosed via megalin include multiple low-molecular weight proteins such as parathyroid hormone, 34 insulin, b 2 -microglobulin, epidermal growth factor, prolactin, lysozyme, cytochrome c, 35 a 1 -microglobulin, odorant-binding protein, 36 transthyretin 37 and leptin. 26 The majority of the ligands that are internalized by megalin are transported via endocytotic vesicles to lysosomes, resulting in their dissociation and degradation.…”

Section: Discussionmentioning

confidence: 99%

Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules

Oyama

Takeda

Hama

et al. 2005

Laboratory Investigation

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Liver-type fatty acid binding protein (L-FABP) binds with high affinity to hydrophobic molecules including free fatty acid, bile acid and bilirubin, which are potentially nephrotoxic, and is involved in their metabolism mainly in hepatocytes. L-FABP is released into the circulation, and patients with liver damage have an elevated plasma L-FABP level. L-FABP is also present in renal tubules; however, the precise localization of L-FABP and its potential role in the renal tubules are not known. In this study, we examined the cellular and subcellular localization of L-FABP in the rat kidney and tried to determine from where the L-FABP in kidney tissues had originated. Immunohistochemical studies of kidney sections localized L-FABP in the lysosomes of proximal tubule cells (PTC). In rats with carbon tetrachloride (CCl 4 )-induced acute liver injury, we detected high levels of L-FABP in the circulation and in the kidney compared with those in the control rat by immunoblotting, while reverse transcription-polymerase chain reaction showed that the level of L-FABP mRNA expression in the kidney of CCl 4 -treated rats was low and did not differ from that in the control rat. When 35 S-L-FABP was intravenously administered to rats, the kidneys took up 35 S-L-FABP more preferentially than the liver and heart, and histoautoradiography of kidney sections revealed that 35 S-L-FABP was internalized via the apical domains of PTC. Quartz-crystal microbalance analysis revealed that L-FABP bound to megalin, a multiligand endocytotic receptor on PTC, in a Ca 2 þ -dependent manner. Degradation assays using megalin-expressing rat yolk sac tumor-derived L2 cells demonstrated that megalin mediated the cellular uptake and catabolism of 125 I-L-FABP. In conclusion, circulatory L-FABP was found to be filtered by glomeruli and internalized by PTC probably via megalin-mediated endocytosis. These results suggest a novel renal uptake pathway for L-FABP, a carrier of hydrophobic molecules, some of which may exert nephrotoxic effects.

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Megalin Antagonizes Activation of the Parathyroid Hormone Receptor

Cited by 110 publications

References 38 publications

Rodent Renal Structure Differs among Species

Rodent Renal Structure Differs among Species

Circulating Forms of Parathyroid Hormone: Peeling Back the Onion

Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules

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