36 results on '"Breiderhoff, Tilman"'
Search Results
2. Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury
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Sieckmann, Tobias, Schley, Gunnar, Ögel, Neslihan, Kelterborn, Simon, Boivin, Felix J., Fähling, Michael, Ashraf, Muhammad I., Reichel, Martin, Vigolo, Emilia, Hartner, Andrea, Lichtenberger, Falk-Bach, Breiderhoff, Tilman, Knauf, Felix, Rosenberger, Christian, Aigner, Felix, Schmidt-Ott, Kai, Scholz, Holger, and Kirschner, Karin M.
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- 2023
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3. Pan-claudin family interactome analysis reveals shared and specific interactions
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Suarez-Artiles, Lorena, Breiderhoff, Tilman, Girardello, Rossana, Gonschior, Hannes, Rodius, Sophie, Lesur, Antoine, Reimer, Ulf, Ramberger, Evelyn, Perez-Hernandez, Daniel, Müller, Dominik, Mertins, Philipp, and Dittmar, Gunnar
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- 2022
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4. Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects
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Franken, Gijs A. C., Seker, Murat, Bos, Caro, Siemons, Laura A. H., van der Eerden, Bram C. J., Christ, Annabel, Hoenderop, Joost G. J., Bindels, René J. M., Müller, Dominik, Breiderhoff, Tilman, and de Baaij, Jeroen H. F.
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- 2021
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5. Urinary Acidification Does Not Explain the Absence of Nephrocalcinosis in a Mouse Model of Familial Hypomagnesaemia with Hypercalciuria and Nephrocalcinosis (FHHNC).
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Al-Shebel, Amr, Michel, Geert, Breiderhoff, Tilman, and Müller, Dominik
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MICE ,CALCIUM oxalate ,KIDNEY calcification ,LABORATORY mice ,HYPOMAGNESEMIA ,ANIMAL disease models ,ACIDIFICATION - Abstract
Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Neuronal Sorting Protein-Related Receptor sorLA/LR11 Regulates Processing of the Amyloid Precursor Protein
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Andersen, Olav M., Reiche, Juliane, Schmidt, Vanessa, Gotthardt, Michael, Spoelgen, Robert, Behlke, Joachim, Breiderhoff, Tilman, Jansen, Pernille, Wu, Xin, Bales, Kelly R., Cappai, Roberto, Masters, Colin L., Gliemann, Jørgen, Mufson, Elliott J., Hyman, Bradley T., Paul, Steven M., Nykjær, Anders, Willnow, Thomas E., and Ingram, Vernon Martin
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- 2005
7. Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na⁺ and Mg 2+ transport
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Milatz, Susanne, Himmerkus, Nina, Wulfmeyer, Vera Christine, Drewell, Hoora, Mutig, Kerim, Hou, Jianghui, Breiderhoff, Tilman, Müller, Dominik, Fromm, Michael, Bleich, Markus, and Günzel, Dorothee
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- 2017
8. Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.
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Kröhn, Laura, Azabdaftari, Aline, Heuberger, Julian, Hudert, Christian, Zilbauer, Matthias, Breiderhoff, Tilman, and Bufler, Philip
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GENE expression ,INTERLEUKIN-37 ,IMMUNE response ,INFLAMMATORY bowel diseases ,TRANSGENE expression - Abstract
Background and Aims: Intestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids. Methods: Murine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors. Results: Expression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-a-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-a-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids. Conclusions: We speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity. [ABSTRACT FROM AUTHOR]
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- 2023
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9. One gene, two paracellular ion channels—claudin-10 in the kidney
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Milatz, Susanne and Breiderhoff, Tilman
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- 2017
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10. Furosemide rescues hypercalciuria in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis model.
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Kriuchkova, Natalia, Breiderhoff, Tilman, Müller, Dominik, Yilmaz, Duygu Elif, Demirci, Hasan, Drewell, Hoora, Günzel, Dorothee, Himmerkus, Nina, Bleich, Markus, Persson, Pontus B., and Mutig, Kerim
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TRP channels , *CARRIER proteins , *HYPOMAGNESEMIA , *FUROSEMIDE , *KIDNEY calcification - Abstract
Aim: Perturbed calcium homeostasis limits life expectancy in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC). This rare disease occurs by loss‐of‐function mutations in CLDN16 or CLDN19 genes, causing impaired paracellular reabsorption of divalent cations along the cortical thick ascending limb (cTAL). Only partial compensation takes place in the ensuing late distal convoluted tubule, connecting tubule, and collecting duct, where the luminal transient receptor potential channel V5 (TRPV5), as well as basolateral plasma membrane calcium ATPase (PMCA) and sodium‐potassium exchanger (NCX1) mediate transcellular Ca2+ reabsorption. The loop diuretic furosemide induces compensatory activation in these distal segments. Normally, furosemide enhances urinary calcium excretion via inhibition of the aforementioned cTAL. As Ca2+ reabsorption in the cTAL is already severely impaired in FHHNC patients, furosemide may alleviate hypercalciuria in this disease by activation of the distal transcellular Ca2+ transport proteins. Methods: Cldn16‐deficient mice (Cldn16−/−) served as a FHHNC model. Wild‐type (WT) and Cldn16−/− mice were treated with furosemide (7 days of 40 mg/kg bw) or vehicle. We assessed renal electrolyte handling (metabolic cages) and key divalent transport proteins. Results: Cldn16−/− mice show higher Ca2+ excretion than WT and compensatory stimulation of Cldn2, TRPV5, and NCX1 at baseline. Furosemide reduced hypercalciuria in Cldn16−/− mice and enhanced TRPV5 and PMCA levels in Cldn16−/− but not in WT mice. Conclusions: Furosemide significantly reduces hypercalciuria, likely via upregulation of luminal and basolateral Ca2+ transport systems in the distal nephron and collecting duct in this model for FHHNC. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis
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Breiderhoff, Tilman, Himmerkus, Nina, Stuiver, Marchel, Mutig, Kerim, Will, Constanze, Meij, Iwan C., Bachmann, Sebastian, Bleich, Markus, Willnow, Thomas E., and Müller, Dominik
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- 2012
12. Unrecognized role of claudin‐10b in basolateral membrane infoldings of the thick ascending limb.
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Quintanova, Catarina, Himmerkus, Nina, Svendsen, Samuel L., von Schwerdtner, Otto, Merkel, Cosima, Pinckert, Lennart, Mutig, Kerim, Breiderhoff, Tilman, Müller, Dominik, Günzel, Dorothee, and Bleich, Markus
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ELECTRON microscopy ,LABORATORY mice ,FLUORESCENCE microscopy ,EXTRACELLULAR space ,KNOCKOUT mice ,TIGHT junctions - Abstract
Claudin‐10b is an important component of the tight junction in the thick ascending limb (TAL) of Henle's loop and allows paracellular sodium transport. In immunofluorescence stainings, claudin‐10b–positive cells exhibited extensive extra staining of basolateral, column‐like structures. The precise localization and function have so far remained elusive. In isolated cortical TAL segments from C57BL/6J mice, kidney‐specific claudin‐10 knockout mice (cKO), and respective litter mates (WT), we investigated the localization and protein expression and function by fluorescence microscopy and electrophysiological measurements. Ultrastructural analysis of TAL in kidney sections was performed by electron microscopy. Claudin‐10b colocalized with the basolateral Na+‐K+ ATPase and the Cl– channel subunit barttin, but the lack of claudin‐10b did not influence the localization or abundance of these proteins. However, the accessibility of the basolateral infolded extracellular space to ouabain or fluorescein was increased by basolateral Ca2+ removal and in the absence of claudin‐10b. Ultrastructural analysis by electron microscopy revealed a widening of basolateral membrane infoldings in cKO in comparison to WT. We hypothesize that claudin‐10b shapes neighboring membrane invaginations by trans interaction to stabilize and facilitate high‐flux salt transport in a water‐tight epithelium. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Impact of claudin‐10 deficiency on amelogenesis: Lesson from a HELIX tooth.
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Obtel, Nicolas, Le Cabec, Adeline, Nguyen, Thè Nghia, Giabicani, Eloise, Van Malderen, Stijn J. M., Garrevoet, Jan, Percot, Aline, Paris, Céline, Dean, Christopher, Hadj‐Rabia, Smail, Houillier, Pascal, Breiderhoff, Tilman, Bardet, Claire, Coradin, Thibaud, Ramirez Rozzi, Fernando, and Chaussain, Catherine
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AMELOBLASTS ,AMELOGENESIS ,LACRIMAL apparatus ,TEETH ,X-ray fluorescence ,TIGHT junctions - Abstract
In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin‐10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron‐based X‐ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations. [ABSTRACT FROM AUTHOR]
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- 2022
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14. Sort1, Encoded by the Cardiovascular Risk Locus 1p13.3, Is a Regulator of Hepatic Lipoprotein Export
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Kjolby, Mads, Andersen, Olav M., Breiderhoff, Tilman, Fjorback, Anja W., Pedersen, Karen Marie, Madsen, Peder, Jansen, Pernille, Heeren, Joerg, Willnow, Thomas E., and Nykjaer, Anders
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- 2010
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15. Targeted deletion of murine cldn16 identifies extra- and intrarenal compensatory mechanisms of [Ca.sup.2+] and [Mg.sup.2+] wasting
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Will, Constanze, Breiderhoff, Tilman, Thumfart, Julia, Stuiver, Marchel, Kopplin, Kathrin, Sommer, Kerstin, Gunzel, Dorothee, Querfeld, Uwe, Meij, Iwan C., Shan, Qixian, Bleich, Markus, Willnow, Thomas E., and Muller, Dominik
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Calcium ions -- Physiological aspects ,Calcium ions -- Research ,Magnesium in the body -- Physiological aspects ,Magnesium in the body -- Research ,Biological transport -- Research ,Biological sciences - Abstract
Claudin-16 (CLDN16) is critical for renal paracellular epithelial transport of [Ca.sup.2+] and [Mg.sup.2+] in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal [Ca.sup.2+] and [Mg.sup.2+] homeostasis and the pathological mechanisms underlying a human disease associated with CLDNI6 dysfunction [familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), OMIM 248250], we generated a mouse model of CLDN16 deficiency. Similar to patients, CLDN16-deficient mice displayed hypercalciuria and hypomagnesemia. Contrary to FHHNC patients, nephrocalcinosis was absent in our model, indicating the existence of compensatory pathways in ion handling in this model. In line with the renal loss of [Ca.sup.2+], compensatory mechanisms like parathyroid hormone and 1,25[(OH).sub.2][D.sub.3] were significantly elevated. Also, gene expression profiling revealed transcriptional upregulation of several [Ca.sup.2+] and [Mg.sup.2+] transport systems including Trpv5, Trpm6, and calbindin-D9k. Induced gene expression was also seen for the transcripts of two putative [Mg.sup.2+] transport proteins, Cnnm2 and Atpl3a4. Moreover, urinary pH was significantly lower when compared with wild-type mice. Taken together, our findings demonstrate that loss of CLDNI6 activity leads to specific alterations in [Ca.sup.2+] and [Mg.sup.2+] homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal [Ca.sup.2+] and [Mg.sup.2+] handling. magnesium; calcium; kidney; tight junction; transgenic animals doi: 10.1152/ajprenal.00499.2009.
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- 2010
16. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury
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Jansen, Pernille, Giehl, Klaus, Nyengaard, Jens R, Teng, Kenneth, Lioubinski, Oleg, Sjoegaard, Susanne S, Breiderhoff, Tilman, Gotthardt, Michael, Lin, Fuyu, Eilers, Andreas, Petersen, Claus M, Lewin, Gary R, Hempstead, Barbara L, Willnow, Thomas E, and Nykjaer, Anders
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- 2007
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17. The Sorting Receptor Sortilin Exhibits a Dual Function in Exocytic Trafficking of Interferon-γ and Granzyme A in T Cells
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Herda, Stefanie, Raczkowski, Friederike, Mittrücker, Hans-Willi, Willimsky, Gerald, Gerlach, Kerstin, Kühl, Anja A., Breiderhoff, Tilman, Willnow, Thomas E., Dörken, Bernd, Höpken, Uta E., and Rehm, Armin
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- 2012
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18. Differential localization patterns of claudin 10, 16, and 19 in human, mouse, and rat renal tubular epithelia.
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Prot-Bertoye, Caroline, Griveau, Camille, Skjødt, Karsten, Cheval, Lydie, Brideau, Gaëlle, Lievre, Loïc, Ferriere, Elsa, Arbaretaz, Floriane, Garbin, Kevin, Zamani, Reza, Marcussen, Niels, Figueres, Lucile, Breiderhoff, Tilman, Muller, Dominik, Bruneval, Patrick, Houillier, Pascal, and Dimke, Henrik
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CLAUDINS ,ICHTHYOSIS ,TIGHT junctions ,GENETIC variation ,LACRIMAL apparatus ,MICE ,RATS - Abstract
Functional properties of the paracellular pathway depend critically on the set of claudins (CLDN) expressed at the tight junction. Two syndromes are causally linked to loss-of-function mutations of claudins: hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX) syndrome caused by genetic variations in the CLDN10 gene and familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by genetic variations in the CLDN16 or CLDN19 genes. All three genes are expressed in the kidney, particularly in the thick ascending limb (TAL). However, localization of these claudins in humans and rodents remains to be delineated in detail. We studied the segmental and subcellular expression of CLDN10, CLDN16, and CLDN19 in both paraffin-embedded and frozen kidney sections from the adult human, mouse, and rat using immunohistochemistry and immunofluorescence, respectively. Here, CLDN10 was present in a subset of medullary and cortical TAL cells, localizing to basolateral domains and tight junctions in human and rodent kidneys. Weak expression was detected at the tight junction of proximal tubular cells. CLDN16 was primarily expressed in a subset of TAL cells in the cortex and outer stripe of outer medulla, restricted to basolateral domains and tight junctional structures in both human and rodent kidneys. CLDN19 predominantly colocalized with CLDN16 in tight junctions and basolateral domains of the TAL but was also found in basolateral and junctional domains in more distal sites. CLDN10 expression at tight junctions almost never overlapped with that of CLND16 and CLDN19, consistent with distinct junctional pathways with different permeation profiles in both human and rodent kidneys. [ABSTRACT FROM AUTHOR]
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- 2021
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19. Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage
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Klar, Joakim, Piontek, Jörg, Milatz, Susanne, Tariq, Muhammad, Jameel, Muhammad, Breiderhoff, Tilman, Schuster, Jens, Fatima, Ambrin, Asif, Maria, Sher, Muhammad, Mäbert, Katrin, Fromm, Anja, Baig, Shahid M., Günzel, Dorothee, and Dahl, Niklas
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Cell Physiology ,lcsh:QH426-470 ,endocrine system diseases ,Cell Membranes ,Materials Science ,Material Properties ,Mutation, Missense ,Research and Analysis Methods ,Kidney ,digestive system ,Physical Chemistry ,Permeability ,Tight Junctions ,Mice ,Exocrine Glands ,Cations ,Medicine and Health Sciences ,Animals ,Humans ,Protein Isoforms ,Renal Insufficiency ,Medicinsk genetik ,Skin ,Ions ,Staining ,Hypohidrosis ,urogenital system ,Biology and Life Sciences ,Membrane Proteins ,Kidneys ,Biological Transport ,Epithelial Cells ,Renal System ,Cell Biology ,Sweat Glands ,Membrane Staining ,lcsh:Genetics ,Chemistry ,Microscopy, Electron ,Specimen Preparation and Treatment ,Physical Sciences ,Claudins ,Anatomy ,Cellular Structures and Organelles ,Integumentary System ,Junctional Complexes ,Medical Genetics ,tissues ,Research Article - Abstract
Claudins constitute the major component of tight junctions and regulate paracellular permeability of epithelia. Claudin-10 occurs in two major isoforms that form paracellular channels with ion selectivity. We report on two families segregating an autosomal recessive disorder characterized by generalized anhidrosis, severe heat intolerance and mild kidney failure. All affected individuals carry a rare homozygous missense mutation c.144C>G, p.(N48K) specific for the claudin-10b isoform. Immunostaining of sweat glands from patients suggested that the disease is associated with reduced levels of claudin-10b in the plasma membranes and in canaliculi of the secretory portion. Expression of claudin-10b N48K in a 3D cell model of sweat secretion indicated perturbed paracellular Na+ transport. Analysis of paracellular permeability revealed that claudin-10b N48K maintained cation over anion selectivity but with a reduced general ion conductance. Furthermore, freeze fracture electron microscopy showed that claudin-10b N48K was associated with impaired tight junction strand formation and altered cis-oligomer formation. These data suggest that claudin-10b N48K causes anhidrosis and our findings are consistent with a combined effect from perturbed TJ function and increased degradation of claudin-10b N48K in the sweat glands. Furthermore, affected individuals present with Mg2+ retention, secondary hyperparathyroidism and mild kidney failure that suggest a disturbed reabsorption of cations in the kidneys. These renal-derived features recapitulate several phenotypic aspects detected in mice with kidney specific loss of both claudin-10 isoforms. Our study adds to the spectrum of phenotypes caused by tight junction proteins and demonstrates a pivotal role for claudin-10b in maintaining paracellular Na+ permeability for sweat production and kidney function., Author summary Claudins are tight junction proteins forming paracellular barriers that are critical for normal development and homeostasis. The tissue specific paracellular barrier properties are determined by the protein composition of tight junctions that regulates the permeability of solutes and water between different compartments of the body. We show, for the first time, that a mutation in claudin-10b, forming paracellular cation channels in different tissues, causes perturbed Na+ selectivity through altered tight junction formation and function as well as increased degradation of the protein. The mutation is associated with the inability to sweat (anhidrosis) and heat intolerance as well as abnormal cation reabsorption, hypermagnesemia and kidney damage. Our combined findings show that the claudin-10b-mediated paracellular Na+ transport is required for normal sweat production and for the regulation of cation homeostasis in the kidneys.
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- 2017
20. Claudin-16 deficiency impairs tight junction function in ameloblasts, leading to abnormal enamel formation
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Bardet, Claire, Courson, Frédéric, Wu, Yong, Khaddam, Mayssam, Salmon, Benjamin, Ribes, Sandy, Thumfart, Julia, Yamaguti, Paulo, Rochefort, Gael, Figueres, Marie-Lucile, Breiderhoff, Tilman, Garcia-Castaño, Alejandro, Vallée, Benoît, Le Denmat, Dominique, Baroukh, Brigitte, Guilbert, Thomas, Schmitt, Alain, Massé, Jean-Marc, Bazin, Dominique, Lorenz, Georg, Morawietz, Maria, Hou, Jianghui, Carvalho-Lobato, Patricia, Manzanares, Maria Cristina, Fricain, Jean-Christophe, Talmud, Déborah, Demontis, Renato, Neves, Francisco, Zenaty, Delphine, Berdal, Ariane, Kiesow, Andreas, Petzold, Matthias, Menashi, Suzanne, Linglart, Agnès, Acevedo, Ana Carolina, Vargas-Poussou, Rosa, Müller, Dominik, Houillier, Pascal, Chaussain, Catherine, Publica, Pathologies, Imagerie et Biothérapies oro-faciales (EA 2496), Université Paris Descartes - Paris 5 (UPD5), Service d'Odontologie [Bretonneau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bretonneau, Centre National de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphore, Hôpital Bretonneau, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory CRRET, Université Paris-Est (UPE), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique des Solides (LPS), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), Spectroscopie, Modélisation, Interfaces pour L'Environnement et la Santé (SMiLES), Laboratoire de Chimie de la Matière Condensée de Paris (LCMCP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC), Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pédiatrie, Centre Hospitalier Régional d'Orléans (CHRO), Group Hospitalier public Sud Oise GHPSO (Creil), Service de pédiatrie générale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Pathologies, Imagerie et Biothérapies oro-faciales ( EA 2496 ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bretonneau, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Est ( UPE ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Physique des Solides ( LPS ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Spectroscopie, Modélisation, Interfaces pour L'Environnement et la Santé ( SMiLES ), Laboratoire de Chimie de la Matière Condensée de Paris ( LCMCP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Centre National de la Recherche Scientifique ( CNRS ), Bioingénierie tissulaire ( BIOTIS ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional d'Orléans ( CHR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bretonneau, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional d'Orléans (CHR), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)
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Adult ,Male ,Amelogenesis Imperfecta ,Syndrome ,Hydrogen-Ion Concentration ,Middle Aged ,Tight Junctions ,Mice ,Young Adult ,stomatognathic diseases ,Phenotype ,stomatognathic system ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,Claudins ,Mutation ,Ameloblasts ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Humans ,Female ,Child ,Dental Enamel ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience; Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients. © 2015 American Society for Bone and Mineral Research.
- Published
- 2016
21. SORCS1 and SORCS3 control energy balance and orexigenic peptide production.
- Author
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Subkhangulova, Aygul, Malik, Anna R., Hermey, Guido, Popp, Oliver, Dittmar, Gunnar, Rathjen, Thomas, Poy, Matthew N., Stumpf, Alexander, Beed, Prateep Sanker, Schmitz, Dietmar, Breiderhoff, Tilman, and Willnow, Thomas E.
- Abstract
Abstract: SORCS1 and SORCS3 are two related sorting receptors expressed in neurons of the arcuate nucleus of the hypothalamus. Using mouse models with individual or dual receptor deficiencies, we document a previously unknown function of these receptors in central control of metabolism. Specifically, SORCS1 and SORCS3 act as intracellular trafficking receptors for tropomyosin‐related kinase B to attenuate signaling by brain‐derived neurotrophic factor, a potent regulator of energy homeostasis. Loss of the joint action of SORCS1 and SORCS3 in mutant mice results in excessive production of the orexigenic neuropeptide agouti‐related peptide and in a state of chronic energy excess characterized by enhanced food intake, decreased locomotor activity, diminished usage of lipids as metabolic fuel, and increased adiposity, albeit at overall reduced body weight. Our findings highlight a novel concept in regulation of the melanocortin system and the role played by trafficking receptors SORCS1 and SORCS3 in this process. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
22. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export
- Author
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Kjølby, Mads Fuglsang, Andersen, Olav Michael, Breiderhoff, Tilman, Fjorback, Anja Nawarecki, Pedersen, Karen-Marie, Madsen, Peder Søndergaard, Jansen, Pernille, Heeren, Jörg, Willnow, Thomas, and Nykjær, Anders
- Subjects
lipids (amino acids, peptides, and proteins) - Abstract
Recent genome-wide association studies (GWAS) have revealed strong association of hypercholesterolemia and myocardial infarction with SNPs on human chromosome 1p13.3. This locus covers three genes: SORT1, CELSR2, and PSRC1. We demonstrate that sortilin, encoded by SORT1, is an intracellular sorting receptor for apolipoprotein (apo) B100. It interacts with apoB100 in the Golgi and facilitates the formation and hepatic export of apoB100-containing lipoproteins, thereby regulating plasma low-density lipoprotein (LDL) cholesterol. Absence of sortilin in gene-targeted mice reduces secretion of lipoproteins from the liver and ameliorates hypercholesterolemia and atherosclerotic lesion formation in LDL receptor-deficient animals. In contrast, sortilin overexpression stimulates hepatic release of lipoproteins and increases plasma LDL levels. Our data have uncovered a regulatory pathway in hepatic lipoprotein export and suggest a molecular explanation for the cardiovascular risk being associated with 1p13.3. Udgivelsesdato: september 8
- Published
- 2010
23. Tu1783 - HDAC as Versatile Regulators of the Intestinal Barrier Integrity and Epithelial Regeneration in Inflammatory Bowel Disease
- Author
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Friedrich, Marie, Ganther, Julia, Breiderhoff, Tilman, Rosenthal, Rita, Glauben, Rainer, and Siegmund, Britta
- Published
- 2017
- Full Text
- View/download PDF
24. Claudin Loss-of-Function Disrupts Tight Junctions and Impairs Amelogenesis.
- Author
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Bardet, Claire, Ribes, Sandy, Yong Wu, Diallo, Mamadou Tidiane, Salmon, Benjamin, Breiderhoff, Tilman, Houillier, Pascal, Müller, Dominik, and Chaussain, Catherine
- Subjects
CLAUDINS ,AMELOGENESIS imperfecta ,LOOP of Henle ,TIGHT junctions ,TOOTH germ (Dentition) - Abstract
Claudins are a family of proteins that forms paracellular barriers and pores determining tight junctions (TJ) permeability. Claudin-16 and -19 are pore forming TJ proteins allowing calcium and magnesium reabsorption in the thick ascending limb of Henle's loop (TAL). Loss-of-function mutations in the encoding genes, initially identified to cause Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC), were recently shown to be also involved in Amelogenesis Imperfecta (AI). In addition, both claudins were expressed in the murine tooth germ and Claudin-16 knockout (KO) mice displayed abnormal enamel formation. Claudin-3, an ubiquitous claudin expressed in epithelia including kidney, acts as a barrier-forming tight junction protein. We determined that, similarly to claudin-16 and claudin-19, claudin-3 was expressed in the tooth germ, more precisely in the TJ located at the apical end of secretory ameloblasts. The observation of Claudin-3 KO teeth revealed enamel defects associated to impaired TJ structure at the secretory ends of ameloblasts and accumulation ofmatrix proteins in the forming enamel. Thus, claudin-3 protein loss-of-function disturbs amelogenesis similarly to claudin-16 loss-of-function, highlighting the importance of claudin proteins for the TJ structure. These findings unravel that loss-of-function of either pore or barrier-forming TJ proteins leads to enamel defects. Hence, the major structural function of claudin proteins appears essential for amelogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
25. Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na+ and Mg2+ transport.
- Author
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Milatz, Susanne, Himmerkus, Nina, Bleich, Markus, Wulfmeyer, Vera Christine, Drewell, Hoora, Mutig, Kerim, Hou, Jianghui, Breiderhoff, Tilman, Fromm, Michael, Günzel, Dorothee, and Müller, Dominik
- Subjects
MOSAICISM ,CLAUDINS ,SPATIAL systems ,LOOP of Henle ,CATION metabolism - Abstract
The thick ascending limb (TAL) of Henle’s loop drives paracellular Na
+ , Ca2+ , and Mg2+ reabsorption via the tight junction (TJ). The TJ is composed of claudins that consist of four transmembrane segments, two extracellular segments (ECS1 and -2), and one intracellular loop. Claudins interact within the same (cis) and opposing (trans) plasma membranes. The claudins Cldn10b, -16, and -19 facilitate cation reabsorption in the TAL, and their absence leads to a severe disturbance of renal ion homeostasis. We combined electrophysiological measurements on microperfused mouse TAL segments with subsequent analysis of claudin expression by immunostaining and confocal microscopy. Claudin interaction properties were examined using heterologous expression in the TJ-free cell line HEK 293, live-cell imaging, and Förster/FRET. To reveal determinants of interaction properties, a set of TAL claudin protein chimeras was created and analyzed. Our main findings are that (i) TAL TJs show a mosaic expression pattern of either cldn10b or cldn3/cldn16/cldn19 in a complex; (ii) TJs dominated by cldn10b prefer Na+ over Mg2+ , whereas TJs dominated by cldn16 favor Mg2+ over Na+ ; (iii) cldn10b does not interact with other TAL claudins, whereas cldn3 and cldn16 can interact with cldn19 to form joint strands; and (iv) further claudin segments in addition to ECS2 are crucial for trans interaction. We suggest the existence of at least two spatially distinct types of paracellular channels in TAL: a cldn10b-based channel for monovalent cations such as Na+ and a spatially distinct site for reabsorption of divalent cations such as Ca2+ and Mg2+ . [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
26. Deletion of claudin-10 [Cldn 10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis.
- Author
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Breiderhoff, Tilman, Himmerkus, Nina, Stuiver, Marchel, Mutig, Kerim, Will, Constanze, Meij, Iwan C., Bachmann, Sebastian, Bleich, Markus, Willnow, Thomas E., and Müller, Dominik
- Subjects
- *
KIDNEY calcification , *TIGHT junctions , *CLAUDINS , *ION transport (Biology) , *PERMEABILITY (Biology) , *LABORATORY mice , *ABSORPTION (Physiology) , *EXTREMITIES (Anatomy) , *PHYSIOLOGICAL effects of sodium , *LEAD & the environment - Abstract
In the kidney, tight junction proteins contribute to segment specific selectivity and permeability of paracellular ¡on transport. In the thick ascending limb (TAL) of Henle's loop, chloride is reabsorbed transcellularly, whereas sodium reabsorption takes transcellular and paracellular routes. TAL salt transport maintains the concentrating ability of the kidney and generates a transepithelial voltage that drives the reabsorption of calcium and magnesium. Thus, functionality of TAL ion transport depends strongly on the properties of the paracellular pathway. To elucidate the role of the tight junction protein claudin-10 in TAL function, we generated mice with a deletion of Cldn10 in this segment. We show that claudin-10 determines paracellular sodium permeability, and that its 10ss leads to hypermagnesemia and nephrocalcinosis. In isolated perfused TAL tubules of claudin-10-deficient mice, paracellular permeability of sodium is decreased, and the relative permeability of calcium and magnesium is increased. Moreover, furosemide-inhibitable transepithelial voltage is increased, leading to a shift from paracellular sodium transport to paracellular hyperabsorption of calcium and magnesium. These data identify claudin-10 as a key factor in control of cation selectivity and transport in the TAL, and deficiency in this pathway as a cause of nephrocalcinosis. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
27. Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting.
- Author
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Will, Constanze, Breiderhoff, Tilman, Thumfart, Julia, Stuiver, Marchel, Kopplin, Kathrin, Sommer, Kerstin, Günzel, Dorothee, Querfeld, Uwe, Meij, Iwan C., Qixian Shan, Bleich, Markus, Willnow, Thomas E., and Müller, Dominik
- Subjects
- *
KIDNEY diseases , *KIDNEY calcification , *MAGNESIUM , *CALCIUM , *CALCIUM regulating hormones , *GENE expression , *PARATHYROID hormone - Abstract
Claudin-16 (CLDN 16) is critical for renal paracellular epithelial transport of Ca2+ and Mg2+ in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal Ca2+ and Mg2+ homeostasis and the pathological mechanisms underlying a human disease associated with CLDN16 dysfunction [familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), OMIM 248250], we generated a mouse model of CLDN16 deficiency. Similar to patients, CLDN16-deficient mice displayed hypercalciuria and hypomagnesemia. Contrary Io FHHNC patients, nephrocalcinosis was absent in our model indicating the existence of compensatory pathways in ion handling in this model. In line with the renal loss of Ca2+, compensation mechanisms like parathyroid hormone and 1,25(OH)2D3 were significantly elevated. Also, gene expression profiling revealed transcriptional upregulation of several Ca2+ and Mg2+ transport systems including Trpv5, Trpm6. and calbindin-D9k. Induced gene expression was also seen for the transcripts of two putative Mg2+ transport proteins, Cnnm2 and Atp13a4. Moreover, urinary pH was significantly lower when compared with wild-type mice. Taken together, our findings demonstrate that loss of CLDN16 activity leads to specific alterations in Ca2+ and Mg2+ homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal Ca2+ and Mg2+ handling. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
28. Sortilin-Related Receptor SORCS3 Is a Postsynaptic Modulator of Synaptic Depression and Fear Extinction.
- Author
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Breiderhoff, Tilman, Christiansen, Gitte B., Pallesen, Lone T., Vaegter, Christian, Nykjaer, Anders, Holm, Mai Marie, Glerup, Simon, and Willnow, Thomas E.
- Subjects
- *
MENTAL depression , *FEAR , *EXTINCTION (Psychology) , *CELLULAR signal transduction , *HIPPOCAMPUS (Brain) , *METHYL aspartate receptors , *LABORATORY mice - Abstract
SORCS3 is an orphan receptor of the VPS10P domain receptor family, a group of sorting and signaling receptors central to many pathways in control of neuronal viability and function. SORCS3 is highly expressed in the CA1 region of the hippocampus, but the relevance of this receptor for hippocampal activity remained absolutely unclear. Here, we show that SORCS3 localizes to the postsynaptic density and that loss of receptor activity in gene-targeted mice abrogates NMDA receptor-dependent and -independent forms of long-term depression (LTD). Consistent with a loss of synaptic retraction, SORCS3-deficient mice suffer from deficits in behavioral activities associated with hippocampal LTD, particularly from an accelerated extinction of fear memory. A possible molecular mechanism for SORCS3 in synaptic depression was suggested by targeted proteomics approaches that identified the ability of SORCS3 to functionally interact with PICK1, an adaptor that sorts glutamate receptors at the postsynapse. Faulty localization of PICK1 in SORCS3-deficient neurons argues for altered glutamate receptor trafficking as the cause of altered synaptic plasticity in the SORCS3-deficient mouse model. In conclusion, our studies have identified a novel function for VPS10P domain receptors in control of synaptic depression and suggest SORCS3 as a novel factor modulating aversive memory extinction. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
29. Hyporesponsiveness to Glucocorticoids in Mice Genetically Deficient for the Corticosteroid Binding Globulin.
- Author
-
Peterson, Helle Heibroch, Andreassen, Thomas K., Breiderhoff, Tilman, Bräsen, Jan Hinrich, Schulz, Herbert, Gross, Volkmar, Gröne, Hermann-Josef, Nykjaer, Anders, and Willnow, Thomas E.
- Subjects
CORTICOSTEROIDS ,GLOBULINS ,GLUCOCORTICOIDS ,BLOOD plasma ,PROTEINS ,SERUM - Abstract
Corticosteroid binding globulin (CBG) is the carrier for glucocorticoids in plasma. The protein is believed to keep the steroids inactive and to regulate the amount of free hormone acting on target tissues (free hormone hypothesis). Here, we generated a mouse model genetically deficient for CBG to test the contribution of the carrier to glucocorticoid action and adrenocortical stress response. The absence of CBG resulted in a lack of corticosterone binding activity in serum and in an ∼10-fold increase in free corticosterone levels in CBG-null mice, consistent with its role in regulation of circulating free hormone levels. Surprisingly, cbg
-/- animals did not exhibit features seen in organisms with enhanced glucocorticoid signaling. Rather, the mice exhibited increased activity of the pituitary axis of hormonal control, normal levels of gluconeogenetic enzymes, and fatigue, as well as an aggravated response to septic shock, indicating an inability to appropriately respond to the excess free corticosterone in the absence of CBG. Thus, our data suggest an active role for CBG in bioavailability, local delivery, and/or cellular signal transduction of glucocorticoids that extends beyond a function as a mere cargo transporter. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
30. Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2.
- Author
-
Giménez-Mascarell, Paula, Oyenarte, Iker, Hardy, Serge, Breiderhoff, Tilman, Stuiver, Marchel, Kostantin, Elie, Diercks, Tammo, Pey, Angel L., Ereño-Orbea, June, Martínez-Chantar, María Luz, Khalaf-Nazza, Reham, Claverie-Martin, Felix, Müller, Dominik, Tremblay, Michel L., and Martínez-Cruz, Luis Alfonso
- Subjects
- *
PHOSPHATASES , *METASTASIS , *LIVER cancer , *CYCLINS , *CYSTATHIONINE beta-synthase - Abstract
Phosphatases of regenerating liver (PRLs), the most oncogenic of all protein-tyrosine phosphatases (PTPs), play a critical role in metastatic progression of cancers. Recent findings established a new paradigm by uncovering that their association with magnesium transporters of the cyclinM(CNNM) family causes a rise in intracellular magnesium levels that promote oncogenic transformation. Recently, however, essential roles for regulation of the circadian rhythm and reproduction of the CNNM family have been highlighted. Here, we describe the crystal structure of PRL-1 in complex with the Bateman module of CNNM2 (CNNM2BAT), which consists of two cystathionine β-synthase (CBS) domains (IPR000664) and represents an intracellular regulatory module of the transporter. The structure reveals a heterotetrameric association, consisting of a disclike homodimer of CNNM2BAT bound to two independent PRL-1 molecules, each one located at opposite tips of the disc. The structure highlights the key role played by Asp-558 at the extended loop of the CBS2 motif of CNNM2 in maintaining the association between the two proteins and proves that the interaction between CNNM2 and PRL-1 occurs via the catalytic domain of the phosphatase. Our data shed new light on the structural basis underlying the interaction between PRL phosphatases and CNNM transporters and provides a hypothesis about the molecular mechanism by which PRL-1, upon binding to CNNM2, might increase the intracellular concentration of Mg2+ thereby contributing to tumor progression and metastasis. The availability of this structure sets the basis for the rational design of compounds modulating PRL-1 andCNNM2activities. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
31. Role of Sortilin in Models of Autoimmune Neuroinflammation.
- Author
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Reuter, Eva, Weber, Juliane, Paterka, Magdalena, Ploen, Robert, Breiderhoff, Tilman, van Horssen, Jack, Willnow, Thomas E., Siffrin, Volker, and Zipp, Frauke
- Subjects
- *
PROTEIN transport , *CELLULAR signal transduction , *DEMENTIA , *DENDRITIC cells , *MACROPHAGES , *MULTIPLE sclerosis , *AUTOIMMUNE diseases - Abstract
The proneurotrophin receptor sortilin is a protein with dual functions, being involved in intracellular protein transport, as well as cellular signal transduction. The relevance of the receptor for various neuronal disorders, such as dementia, seizures, and brain injury, is well established. In contrast, little is known about the role of sortilin in immune cells and inflammatory diseases. The aim of our study was to elucidate the distribution of sortilin in different immune cell types in mice and humans and to analyze its function in autoimmune CNS inflammation. Sortilin was expressed most profoundly in murine and human macrophages and dendritic cells and to a much lesser extent in B and T cells. In dendritic cells, sortilin had an impact on Ag processing. Accordingly, sortilin was highly expressed by infiltrated perivascular myeloid cells, mainly in vessel cuffs, in the CNS of patients suffering from multiple sclerosis, the most common inflammatory autoimmune disease of the CNS. Yet, sortilin gene-targeted mice (Sort1-/-) and chimeras deficient in sortilin in the immune system were as susceptible as wild-type littermates to T cell-dependent experimental autoimmune encephalomyelitis. Considering our results and recent data from other investigators, we conclude that the proneurotrophin receptor sortilin plays a role in innate, rather than in adaptive, immune processes and, thus, not in autoimmune neuroinflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
32. Claudin-10a Deficiency Shifts Proximal Tubular Cl - Permeability to Cation Selectivity via Claudin-2 Redistribution.
- Author
-
Breiderhoff T, Himmerkus N, Meoli L, Fromm A, Sewerin S, Kriuchkova N, Nagel O, Ladilov Y, Krug SM, Quintanova C, Stumpp M, Garbe-Schönberg D, Westernströer U, Merkel C, Brinkhus MA, Altmüller J, Schweiger MR, Müller D, Mutig K, Morawski M, Halbritter J, Milatz S, Bleich M, and Günzel D
- Subjects
- Animals, Cations metabolism, Kidney Tubules, Proximal metabolism, Mice, Permeability, Tight Junctions physiology, Claudin-2, Claudins metabolism
- Abstract
Background: The tight junction proteins claudin-2 and claudin-10a form paracellular cation and anion channels, respectively, and are expressed in the proximal tubule. However, the physiologic role of claudin-10a in the kidney has been unclear., Methods: To investigate the physiologic role of claudin-10a, we generated claudin-10a-deficient mice, confirmed successful knockout by Southern blot, Western blot, and immunofluorescence staining, and analyzed urine and serum of knockout and wild-type animals. We also used electrophysiologic studies to investigate the functionality of isolated proximal tubules, and studied compensatory regulation by pharmacologic intervention, RNA sequencing analysis, Western blot, immunofluorescence staining, and respirometry., Results: Mice deficient in claudin-10a were fertile and without overt phenotypes. On knockout, claudin-10a was replaced by claudin-2 in all proximal tubule segments. Electrophysiology showed conversion from paracellular anion preference to cation preference and a loss of paracellular Cl
- over HCO3 - preference. As a result, there was tubular retention of calcium and magnesium, higher urine pH, and mild hypermagnesemia. A comparison with other urine and serum parameters under control conditions and sequential pharmacologic transport inhibition, and unchanged fractional lithium excretion, suggested compensative measures in proximal and distal tubular segments. Changes in proximal tubular oxygen handling and differential expression of genes regulating fatty acid metabolism indicated proximal tubular adaptation. Western blot and immunofluorescence revealed alterations in distal tubular transport., Conclusions: Claudin-10a is the major paracellular anion channel in the proximal tubule and its deletion causes calcium and magnesium hyper-reabsorption by claudin-2 redistribution. Transcellular transport in proximal and distal segments and proximal tubular metabolic adaptation compensate for loss of paracellular anion permeability., (Copyright © 2022 by the American Society of Nephrology.)- Published
- 2022
- Full Text
- View/download PDF
33. Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria.
- Author
-
Breiderhoff T, Himmerkus N, Drewell H, Plain A, Günzel D, Mutig K, Willnow TE, Müller D, and Bleich M
- Subjects
- Animals, Calcium metabolism, Claudins genetics, Disease Models, Animal, Gene Deletion, Genetic Predisposition to Disease, Hypercalciuria genetics, Hypercalciuria metabolism, Hypercalciuria physiopathology, Kidney Tubules, Distal pathology, Kidney Tubules, Distal physiopathology, Loop of Henle pathology, Loop of Henle physiopathology, Magnesium metabolism, Magnesium Deficiency genetics, Magnesium Deficiency metabolism, Magnesium Deficiency physiopathology, Mice, Inbred C57BL, Mice, Knockout, Nephrocalcinosis genetics, Nephrocalcinosis metabolism, Nephrocalcinosis physiopathology, Nephrocalcinosis prevention & control, Phenotype, Sodium metabolism, Claudins deficiency, Hypercalciuria prevention & control, Kidney Tubules, Distal metabolism, Loop of Henle metabolism, Magnesium Deficiency prevention & control
- Abstract
The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
34. Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na+ and Mg2+ transport.
- Author
-
Milatz S, Himmerkus N, Wulfmeyer VC, Drewell H, Mutig K, Hou J, Breiderhoff T, Müller D, Fromm M, Bleich M, and Günzel D
- Subjects
- Animals, Claudins genetics, HEK293 Cells, Humans, Loop of Henle physiology, Mice, Inbred C57BL, Mice, Knockout, Rats, Sprague-Dawley, Tight Junctions metabolism, Claudins metabolism, Loop of Henle metabolism, Magnesium metabolism, Sodium metabolism
- Abstract
The thick ascending limb (TAL) of Henle's loop drives paracellular Na
+ , Ca2+ , and Mg2+ reabsorption via the tight junction (TJ). The TJ is composed of claudins that consist of four transmembrane segments, two extracellular segments (ECS1 and -2), and one intracellular loop. Claudins interact within the same (cis) and opposing (trans) plasma membranes. The claudins Cldn10b, -16, and -19 facilitate cation reabsorption in the TAL, and their absence leads to a severe disturbance of renal ion homeostasis. We combined electrophysiological measurements on microperfused mouse TAL segments with subsequent analysis of claudin expression by immunostaining and confocal microscopy. Claudin interaction properties were examined using heterologous expression in the TJ-free cell line HEK 293, live-cell imaging, and Förster/FRET. To reveal determinants of interaction properties, a set of TAL claudin protein chimeras was created and analyzed. Our main findings are that (i) TAL TJs show a mosaic expression pattern of either cldn10b or cldn3/cldn16/cldn19 in a complex; (ii) TJs dominated by cldn10b prefer Na+ over Mg2+ , whereas TJs dominated by cldn16 favor Mg2+ over Na+ ; (iii) cldn10b does not interact with other TAL claudins, whereas cldn3 and cldn16 can interact with cldn19 to form joint strands; and (iv) further claudin segments in addition to ECS2 are crucial for trans interaction. We suggest the existence of at least two spatially distinct types of paracellular channels in TAL: a cldn10b-based channel for monovalent cations such as Na+ and a spatially distinct site for reabsorption of divalent cations such as Ca2+ and Mg2 ., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
- Full Text
- View/download PDF
35. Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation.
- Author
-
Bardet C, Courson F, Wu Y, Khaddam M, Salmon B, Ribes S, Thumfart J, Yamaguti PM, Rochefort GY, Figueres ML, Breiderhoff T, Garcia-Castaño A, Vallée B, Le Denmat D, Baroukh B, Guilbert T, Schmitt A, Massé JM, Bazin D, Lorenz G, Morawietz M, Hou J, Carvalho-Lobato P, Manzanares MC, Fricain JC, Talmud D, Demontis R, Neves F, Zenaty D, Berdal A, Kiesow A, Petzold M, Menashi S, Linglart A, Acevedo AC, Vargas-Poussou R, Müller D, Houillier P, and Chaussain C
- Subjects
- Adult, Ameloblasts pathology, Amelogenesis Imperfecta metabolism, Amelogenesis Imperfecta pathology, Animals, Child, Claudins genetics, Dental Enamel pathology, Female, Humans, Hydrogen-Ion Concentration, Male, Mice, Middle Aged, Mutation genetics, Phenotype, Syndrome, Young Adult, Ameloblasts metabolism, Claudins deficiency, Dental Enamel abnormalities, Dental Enamel metabolism, Tight Junctions metabolism
- Abstract
Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients., (© 2015 American Society for Bone and Mineral Research.)
- Published
- 2016
- Full Text
- View/download PDF
36. Hyporesponsiveness to glucocorticoids in mice genetically deficient for the corticosteroid binding globulin.
- Author
-
Petersen HH, Andreassen TK, Breiderhoff T, Bräsen JH, Schulz H, Gross V, Gröne HJ, Nykjaer A, and Willnow TE
- Subjects
- Adrenocorticotropic Hormone blood, Animals, Body Weight, Corticosterone blood, Exons genetics, Female, Food Deprivation, Gene Expression, Gene Targeting, Glucocorticoids pharmacology, Inflammation immunology, Injections, Intraperitoneal, Kidney cytology, Lipopolysaccharides immunology, Liver cytology, Male, Mice, Survival Rate, Glucocorticoids metabolism, Transcortin deficiency, Transcortin metabolism
- Abstract
Corticosteroid binding globulin (CBG) is the carrier for glucocorticoids in plasma. The protein is believed to keep the steroids inactive and to regulate the amount of free hormone acting on target tissues (free hormone hypothesis). Here, we generated a mouse model genetically deficient for CBG to test the contribution of the carrier to glucocorticoid action and adrenocortical stress response. The absence of CBG resulted in a lack of corticosterone binding activity in serum and in an approximately 10-fold increase in free corticosterone levels in CBG-null mice, consistent with its role in regulation of circulating free hormone levels. Surprisingly, cbg(-/-) animals did not exhibit features seen in organisms with enhanced glucocorticoid signaling. Rather, the mice exhibited increased activity of the pituitary axis of hormonal control, normal levels of gluconeogenetic enzymes, and fatigue, as well as an aggravated response to septic shock, indicating an inability to appropriately respond to the excess free corticosterone in the absence of CBG. Thus, our data suggest an active role for CBG in bioavailability, local delivery, and/or cellular signal transduction of glucocorticoids that extends beyond a function as a mere cargo transporter.
- Published
- 2006
- Full Text
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