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2. Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury

Author

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.

Published
2023
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13. Impact of claudin‐10 deficiency on amelogenesis: Lesson from a HELIX tooth

Author

Obtel, Nicolas, primary, Le Cabec, Adeline, additional, Nguyen, Thè Nghia, additional, Giabicani, Eloise, additional, Van Malderen, Stijn J. M., additional, Garrevoet, Jan, additional, Percot, Aline, additional, Paris, Céline, additional, Dean, Christopher, additional, Hadj‐Rabia, Smail, additional, Houillier, Pascal, additional, Breiderhoff, Tilman, additional, Bardet, Claire, additional, Coradin, Thibaud, additional, Ramirez Rozzi, Fernando, additional, and Chaussain, Catherine, additional

Published
2022
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14. Claudin-10a Deficiency Shifts Proximal Tubular Cl- Permeability to Cation Selectivity via Claudin-2 Redistribution

Author

Breiderhoff, Tilman, Himmerkus, Nina, Meoli, Luca, Fromm, Anja, Sewerin, Sebastian, Kriuchkova, Natalia, Nagel, Oliver, Ladilov, Yury, Krug, Susanne M., Quintanova, Catarina, Stumpp, Meike, Garbe-Schoenberg, Dieter, Westernstroeer, Ulrike, Merkel, Cosima, Brinkhus, Merle Annette, Altmuller, Janine, Schweiger, Michal R., Muller, Dominik, Mutig, Kerim, Morawski, Markus, Halbritter, Jan, Milatz, Susanne, Bleich, Markus, Guenzel, Dorothee, Breiderhoff, Tilman, Himmerkus, Nina, Meoli, Luca, Fromm, Anja, Sewerin, Sebastian, Kriuchkova, Natalia, Nagel, Oliver, Ladilov, Yury, Krug, Susanne M., Quintanova, Catarina, Stumpp, Meike, Garbe-Schoenberg, Dieter, Westernstroeer, Ulrike, Merkel, Cosima, Brinkhus, Merle Annette, Altmuller, Janine, Schweiger, Michal R., Muller, Dominik, Mutig, Kerim, Morawski, Markus, Halbritter, Jan, Milatz, Susanne, Bleich, Markus, and Guenzel, Dorothee

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.

Published
2022

15. Claudin-10a Deficiency Shifts Proximal Tubular Cl- Permeability to Cation Selectivity via Claudin-2 Redistribution

Author

Breiderhoff, Tilman, primary, Himmerkus, Nina, additional, Meoli, Luca, additional, Fromm, Anja, additional, Sewerin, Sebastian, additional, Kriuchkova, Natalia, additional, Nagel, Oliver, additional, Ladilov, Yury, additional, Krug, Susanne M., additional, Quintanova, Catarina, additional, Stumpp, Meike, additional, Garbe-Schönberg, Dieter, additional, Westernströer, Ulrike, additional, Merkel, Cosima, additional, Brinkhus, Merle Annette, additional, Altmüller, Janine, additional, Schweiger, Michal R., additional, Müller, Dominik, additional, Mutig, Kerim, additional, Morawski, Markus, additional, Halbritter, Jan, additional, Milatz, Susanne, additional, Bleich, Markus, additional, and Günzel, Dorothee, additional

Published
2022
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16. Differential localization patterns of claudin 10, 16, and 19 in human, mouse, and rat renal tubular epithelia

Author

Prot-Bertoye, Caroline, primary, Griveau, Camille, additional, Skjødt, Karsten, additional, Cheval, Lydie, additional, Brideau, Gaëlle, additional, Lievre, Loïc, additional, Ferriere, Elsa, additional, Arbaretaz, Floriane, additional, Garbin, Kevin, additional, Zamani, Reza, additional, Marcussen, Niels, additional, Figueres, Lucile, additional, Breiderhoff, Tilman, additional, Muller, Dominik, additional, Bruneval, Patrick, additional, Houillier, Pascal, additional, and Dimke, Henrik, additional

Published
2021
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17. Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects

Author

Franken, G.A.C., Seker, Murat, Bos, C., Siemons, Laura A.H., Eerden, B.C. van der, Christ, Annabel, Hoenderop, J.G.J., Bindels, R.J.M., Breiderhoff, Tilman, Baaij, J.H.F. de, Franken, G.A.C., Seker, Murat, Bos, C., Siemons, Laura A.H., Eerden, B.C. van der, Christ, Annabel, Hoenderop, J.G.J., Bindels, R.J.M., Breiderhoff, Tilman, and Baaij, J.H.F. de

Abstract

Contains fulltext : 233470.pdf (Publisher’s version ) (Open Access)

Published
2021

18. Claudin-10a Deficiency Shifts Proximal Tubular Cl-Permeability to Cation Selectivity viaClaudin-2 Redistribution

Author

Breiderhoff, Tilman, Himmerkus, Nina, Meoli, Luca, Fromm, Anja, Sewerin, Sebastian, Kriuchkova, Natalia, Nagel, Oliver, Ladilov, Yury, Krug, Susanne M., Quintanova, Catarina, Stumpp, Meike, Garbe-Sch?nberg, Dieter, Westernstr?er, Ulrike, Merkel, Cosima, Brinkhus, Merle Annette, Altm?ller, Janine, Schweiger, Michal R., M?ller, Dominik, Mutig, Kerim, Morawski, Markus, Halbritter, Jan, Milatz, Susanne, Bleich, Markus, and G?nzel, Dorothee

Abstract

Claudin-10 is a tight junction protein expressed along the nephron. The claudin-10a isoform is a paracellular anion channel; claudin-10b facilitates paracellular Na+transport in the thick ascending limb. Mutations in the CLDN10gene that affect either claudin-10b or both isoforms cause HELIX syndrome. This study demonstrates that claudin-10a is essential for paracellular Cl-transport in the proximal tubule. In mice lacking claudin-10a, additional cation-selective claudin-2 incorporates into proximal tubule tight junctions. This turns paracellular anion into cation preference, with renal retention of calcium and magnesium and hypermagnesemia. Loss of anion permeability triggers compensation measures within the proximal tubule and in more distal parts of the nephron. Data from the claudin-10a?deficient mouse suggest mutations affecting both isoforms may result in a more severe electrolyte imbalance in HELIX syndrome.

Published
2022
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19. Differential localization patterns of claudin 10, 16, and 19 in human, mouse, and rat renal tubular epithelia.

Author

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

Subjects
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]

Published
2021
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20. Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage

Author

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

Subjects
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.

Published
2017

22. SORCS 1 and SORCS 3 control energy balance and orexigenic peptide production

Author

Subkhangulova, Aygul, primary, Malik, Anna R, additional, Hermey, Guido, additional, Popp, Oliver, additional, Dittmar, Gunnar, additional, Rathjen, Thomas, additional, Poy, Matthew N, additional, Stumpf, Alexander, additional, Beed, Prateep Sanker, additional, Schmitz, Dietmar, additional, Breiderhoff, Tilman, additional, and Willnow, Thomas E, additional

Published
2018
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23. Claudin-16 deficiency impairs tight junction function in ameloblasts, leading to abnormal enamel formation

Author

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)

Subjects
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

26. Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2

Author

Giménez-Mascarell, Paula, primary, Oyenarte, Iker, additional, Hardy, Serge, additional, Breiderhoff, Tilman, additional, Stuiver, Marchel, additional, Kostantin, Elie, additional, Diercks, Tammo, additional, Pey, Angel L., additional, Ereño-Orbea, June, additional, Martínez-Chantar, María Luz, additional, Khalaf-Nazzal, Reham, additional, Claverie-Martin, Felix, additional, Müller, Dominik, additional, Tremblay, Michel L., additional, and Martínez-Cruz, Luis Alfonso, additional

Published
2017
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27. Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na + and Mg 2+ transport

Author

Milatz, Susanne, primary, Himmerkus, Nina, additional, Wulfmeyer, Vera Christine, additional, Drewell, Hoora, additional, Mutig, Kerim, additional, Hou, Jianghui, additional, Breiderhoff, Tilman, additional, Müller, Dominik, additional, Fromm, Michael, additional, Bleich, Markus, additional, and Günzel, Dorothee, additional

Published
2016
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29. Role of Sortilin in Models of Autoimmune Neuroinflammation

Author

Reuter, Eva, primary, Weber, Juliane, additional, Paterka, Magdalena, additional, Ploen, Robert, additional, Breiderhoff, Tilman, additional, van Horssen, Jack, additional, Willnow, Thomas E., additional, Siffrin, Volker, additional, and Zipp, Frauke, additional

Published
2015
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30. Claudin‐16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation

Author

Bardet, Claire, primary, Courson, Frédéric, additional, Wu, Yong, additional, Khaddam, Mayssam, additional, Salmon, Benjamin, additional, Ribes, Sandy, additional, Thumfart, Julia, additional, Yamaguti, Paulo M, additional, Rochefort, Gael Y, additional, Figueres, Marie‐Lucile, additional, Breiderhoff, Tilman, additional, Garcia‐Castaño, Alejandro, additional, Vallée, Benoit, additional, Le Denmat, Dominique, additional, Baroukh, Brigitte, additional, Guilbert, Thomas, additional, Schmitt, Alain, additional, Massé, Jean‐Marc, additional, Bazin, Dominique, additional, Lorenz, Georg, additional, Morawietz, Maria, additional, Hou, Jianghui, additional, Carvalho‐Lobato, Patricia, additional, Manzanares, Maria Cristina, additional, Fricain, Jean‐Christophe, additional, Talmud, Deborah, additional, Demontis, Renato, additional, Neves, Francisco, additional, Zenaty, Delphine, additional, Berdal, Ariane, additional, Kiesow, Andreas, additional, Petzold, Matthias, additional, Menashi, Suzanne, additional, Linglart, Agnes, additional, Acevedo, Ana Carolina, additional, Vargas‐Poussou, Rosa, additional, Müller, Dominik, additional, Houillier, Pascal, additional, and Chaussain, Catherine, additional

Published
2015
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32. Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na+ and Mg2+ transport.

Author

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
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33. 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 + , Ca 2+ , and Mg 2+ 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 Mg 2+ , whereas TJs dominated by cldn16 favor Mg 2+ 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 Ca 2+ and Mg 2 ., Competing Interests: The authors declare no conflict of interest.

Published
2017
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34. 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
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