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137 results on '"Keck, Mathilde"'

1. A Snake Toxin Derivative for Treatment of Hyponatremia and Polycystic Kidney Diseases

Author

Stanajic-Petrovic, Goran, Keck, Mathilde, Barbe, Peggy, Urman, Apolline, Correia, Evelyne, Isnard, Pierre, Duong Van Huyen, Jean-Paul, Chmeis, Khawla, Diarra, Sékou Siramakan, Palea, Stefano, Theodoro, Frederic, Nguyen, Anvi-Laëtitia, Castelli, Florence, Pruvost, Alain, Zhao, Wenchao, Mendre, Christiane, Mouillac, Bernard, Bienaimé, Frank, Robin, Philippe, Kessler, Pascal, Llorens-Cortes, Catherine, Servent, Denis, Nozach, Hervé, Maillère, Bernard, Guo, Dong, Truillet, Charles, and Gilles, Nicolas

Published
2024
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2. LIT01-196, a Metabolically Stable Apelin-17 Analog, Normalizes Blood Pressure in Hypertensive DOCA-Salt Rats via a NO Synthase-dependent Mechanism

Author

Flahault, Adrien, Keck, Mathilde, Girault-Sotias, Pierre-Emmanuel, Esteoulle, Lucie, de Mota, Nadia, Bonnet, Dominique, and Llorens-Cortes, Catherine

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

Apelin is a neuro-vasoactive peptide that plays a major role in the control of cardiovascular functions and water balance, but has an in-vivo half-life in the minute range, limiting its therapeutic use. We previously developed LIT01-196, a systemically active metabolically stable apelin-17 analog, produced by chemical addition of a fluorocarbon chain to the N-terminal part of apelin-17. LIT01-196 behaves as a potent full agonist for the apelin receptor and has an in vivo half-life in the bloodstream of 28 min after intravenous (i.v.) and 156 min after subcutaneous (s.c.) administrations in conscious normotensive rats. We aimed to investigate the effects of LIT01-196 following systemic administrations on arterial blood pressure, heart rate, fluid balance and electrolytes in conscious normotensive and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. Acute i.v. LIT01-196 administration, in increasing doses, dose-dependently decreases arterial blood pressure with ED 50 values of 9.8 and 3.1 nmol/kg in normotensive and hypertensive rats, respectively. This effect occurs for both via a nitric oxide-dependent mechanism. Moreover, acute s.c. LIT01-196 administration (90 nmol/kg) normalizes arterial blood pressure in conscious hypertensive DOCA-salt rats for more than 7 h. The LIT01-196-induced blood pressure decrease remains unchanged after 4 consecutive daily s.c. administrations of 90 nmol/kg, and does not induce any alteration of plasma sodium and potassium levels and kidney function as shown by the lack of change in plasma creatinine and urea nitrogen levels. Activating the apelin receptor with LIT01-196 may constitute a novel approach for the treatment of hypertension.

Published
2022
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3. Environmental and Health Impacts of Graphene and Other Two-Dimensional Materials: A Graphene Flagship Perspective

Author

European Commission, Centre National de la Recherche Scientifique (France), Commissariat à l’Energie Atomique et aux Energies Alternatives (France), Swiss National Science Foundation, Comunidad de Madrid, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Junta de Comunidades de Castilla-La Mancha, Buerki-Thurnherr, Tina [0000-0003-3723-6562], Wick, Peter [0000-0002-0079-4344], Pelin, Marco [0000-0002-4306-7411], Tubaro, Aurelia [0000-0003-2773-2589], Candotto Carniel, F. [0000-0002-8277-4725], Tretiach, M. [0000-0002-0529-1359], Flahaut, E. [0000-0001-8344-6902], Iglesias, Daniel [0000-0002-1998-0518], Vázquez, Ester [0000-0003-3223-8024], Cellot, Giada [0000-0001-9198-8402], Ballerini, Laura [0000-0001-8420-0787], Castagnola, Valentina [0000-0002-8651-5958], Benfenati, Fabio [0000-0002-0653-8368], Armirotti, Andrea [0000-0002-3766-8755], Sallustrau, Antoine [0000-0001-7118-9224], Taran, Frédéric [0000-0001-5461-329X], Keck, Mathilde [0000-0003-4717-3446], Bussy, Cyrill [0000-0001-8870-443X], Vranic, Sandra [0000-0002-6653-7156], Kostarelos, Kostas [0000-0002-2224-6672], Navas Antón, José María [0000-0002-7644-8499], Mouchet, F. [0000-0003-1993-8448], Suarez-Merino, Blanca [0000-0002-0201-265X], Kanerva, Tomi [0000-0003-2245-1921], Prato, Maurizio [0000-0002-8869-8612], Fadeel, Bengt [0000-0001-5559-8482], Bianco, Alberto [0000-0002-1090-296X], Lin, Hazel, Buerki-Thurnherr, Tina, Kaur, Jasreen, Wick, Peter, Pelin, Marco, Tubaro, Aurelia, Candotto Carniel, F., Tretiach, M., Flahaut, E., Iglesias, Daniel, Vázquez, Ester, Cellot, Giada, Ballerini, Laura, Castagnola, Valentina, Benfenati, Fabio, Armirotti, Andrea, Sallustrau, Antoine, Taran, Frédéric, Keck, Mathilde, Bussy, Cyrill, Vranic, Sandra, Kostarelos, Kostas, Connolly, Mona, Navas Antón, José María, Mouchet, F., Gauthier, L., Baker, James, Suarez-Merino, Blanca, Kanerva, Tomi, Prato, Maurizio, Fadeel, Bengt, Bianco, Alberto, European Commission, Centre National de la Recherche Scientifique (France), Commissariat à l’Energie Atomique et aux Energies Alternatives (France), Swiss National Science Foundation, Comunidad de Madrid, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Junta de Comunidades de Castilla-La Mancha, Buerki-Thurnherr, Tina [0000-0003-3723-6562], Wick, Peter [0000-0002-0079-4344], Pelin, Marco [0000-0002-4306-7411], Tubaro, Aurelia [0000-0003-2773-2589], Candotto Carniel, F. [0000-0002-8277-4725], Tretiach, M. [0000-0002-0529-1359], Flahaut, E. [0000-0001-8344-6902], Iglesias, Daniel [0000-0002-1998-0518], Vázquez, Ester [0000-0003-3223-8024], Cellot, Giada [0000-0001-9198-8402], Ballerini, Laura [0000-0001-8420-0787], Castagnola, Valentina [0000-0002-8651-5958], Benfenati, Fabio [0000-0002-0653-8368], Armirotti, Andrea [0000-0002-3766-8755], Sallustrau, Antoine [0000-0001-7118-9224], Taran, Frédéric [0000-0001-5461-329X], Keck, Mathilde [0000-0003-4717-3446], Bussy, Cyrill [0000-0001-8870-443X], Vranic, Sandra [0000-0002-6653-7156], Kostarelos, Kostas [0000-0002-2224-6672], Navas Antón, José María [0000-0002-7644-8499], Mouchet, F. [0000-0003-1993-8448], Suarez-Merino, Blanca [0000-0002-0201-265X], Kanerva, Tomi [0000-0003-2245-1921], Prato, Maurizio [0000-0002-8869-8612], Fadeel, Bengt [0000-0001-5559-8482], Bianco, Alberto [0000-0002-1090-296X], Lin, Hazel, Buerki-Thurnherr, Tina, Kaur, Jasreen, Wick, Peter, Pelin, Marco, Tubaro, Aurelia, Candotto Carniel, F., Tretiach, M., Flahaut, E., Iglesias, Daniel, Vázquez, Ester, Cellot, Giada, Ballerini, Laura, Castagnola, Valentina, Benfenati, Fabio, Armirotti, Andrea, Sallustrau, Antoine, Taran, Frédéric, Keck, Mathilde, Bussy, Cyrill, Vranic, Sandra, Kostarelos, Kostas, Connolly, Mona, Navas Antón, José María, Mouchet, F., Gauthier, L., Baker, James, Suarez-Merino, Blanca, Kanerva, Tomi, Prato, Maurizio, Fadeel, Bengt, and Bianco, Alberto

Abstract

Two-dimensional (2D) materials have attracted tremendous interest ever since the isolation of atomically thin sheets of graphene in 2004 due to the specific and versatile properties of these materials. However, the increasing production and use of 2D materials necessitate a thorough evaluation of the potential impact on human health and the environment. Furthermore, harmonized test protocols are needed with which to assess the safety of 2D materials. The Graphene Flagship project (2013-2023), funded by the European Commission, addressed the identification of the possible hazard of graphene-based materials as well as emerging 2D materials including transition metal dichalcogenides, hexagonal boron nitride, and others. Additionally, so-called green chemistry approaches were explored to achieve the goal of a safe and sustainable production and use of this fascinating family of nanomaterials. The present review provides a compact survey of the findings and the lessons learned in the Graphene Flagship.

Published
2024

4. C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus

Author

Wu, Yu, Mahtal, Nassim, Paillares, Eléa, Swistak, Léa, Sagadiev, Sara, Acharya, Mridu, Demeret, Caroline, Werf, Sylvie Van Der, Guivel-Benhassine, Florence, Schwartz, Olivier, Petracchini, Serena, Mettouchi, Amel, Caramelle, Lucie, Couvineau, Pierre, Thai, Robert, Barbe, Peggy, Keck, Mathilde, Brodin, Priscille, Machelart, Arnaud, Sencio, Valentin, Trottein, François, Sachse, Martin, Chicanne, Gaëtan, Payrastre, Bernard, Ville, Florian, Kreis, Victor, Popoff, Michel-Robert, Johannes, Ludger, Cintrat, Jean-Christophe, Barbier, Julien, Gillet, Daniel, and Lemichez, Emmanuel

Published
2022
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8. Environmental and Health Impacts of Graphene and Other Two-Dimensional Materials: A Graphene Flagship Perspective

Author

Lin, Hazel, primary, Buerki-Thurnherr, Tina, additional, Kaur, Jasreen, additional, Wick, Peter, additional, Pelin, Marco, additional, Tubaro, Aurelia, additional, Carniel, Fabio Candotto, additional, Tretiach, Mauro, additional, Flahaut, Emmanuel, additional, Iglesias, Daniel, additional, Vázquez, Ester, additional, Cellot, Giada, additional, Ballerini, Laura, additional, Castagnola, Valentina, additional, Benfenati, Fabio, additional, Armirotti, Andrea, additional, Sallustrau, Antoine, additional, Taran, Frédéric, additional, Keck, Mathilde, additional, Bussy, Cyrill, additional, Vranic, Sandra, additional, Kostarelos, Kostas, additional, Connolly, Mona, additional, Navas, José Maria, additional, Mouchet, Florence, additional, Gauthier, Laury, additional, Baker, James, additional, Suarez-Merino, Blanca, additional, Kanerva, Tomi, additional, Prato, Maurizio, additional, Fadeel, Bengt, additional, and Bianco, Alberto, additional

Published
2024
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12. A New Derivative of Retro-2 Displays Antiviral Activity against Respiratory Syncytial Virus

Author

Le Rouzic, Adrien, primary, Fix, Jenna, additional, Vinck, Robin, additional, Kappler-Gratias, Sandrine, additional, Volmer, Romain, additional, Gallardo, Franck, additional, Eléouët, Jean-François, additional, Keck, Mathilde, additional, Cintrat, Jean-Christophe, additional, Barbier, Julien, additional, Gillet, Daniel, additional, and Galloux, Marie, additional

Published
2023
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13. A New Derivative of Retro-2 Displays Antiviral Activity against Respiratory Syncytial Virus.

Author

Le Rouzic, Adrien, Fix, Jenna, Vinck, Robin, Kappler-Gratias, Sandrine, Volmer, Romain, Gallardo, Franck, Eléouët, Jean-François, Keck, Mathilde, Cintrat, Jean-Christophe, Barbier, Julien, Gillet, Daniel, and Galloux, Marie

Subjects
RESPIRATORY syncytial virus, CELL culture, MEMBRANE glycoproteins, CELL membranes, RESPIRATORY infections, VIRAL transmission
Abstract

Human respiratory syncytial virus (hRSV) is the most common cause of bronchiolitis and pneumonia in newborns, with all children being infected before the age of two. Reinfections are very common throughout life and can cause severe respiratory infections in the elderly and immunocompromised adults. Although vaccines and preventive antibodies have recently been licensed for use in specific subpopulations of patients, there is still no therapeutic treatment commonly available for these infections. Here, we investigated the potential antiviral activity of Retro-2.2, a derivative of the cellular retrograde transport inhibitor Retro-2, against hRSV. We show that Retro-2.2 inhibits hRSV replication in cell culture and impairs the ability of hRSV to form syncytia. Our results suggest that Retro-2.2 treatment affects virus spread by disrupting the trafficking of the viral de novo synthetized F and G glycoproteins to the plasma membrane, leading to a defect in virion morphogenesis. Taken together, our data show that targeting intracellular transport may be an effective strategy against hRSV infection. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Acute Effects of Brevetoxin-3 Administered via Oral Gavage to Mice.

Author

Barbe, Peggy, Molgó, Jordi, Thai, Robert, Urman, Apolline, Servent, Denis, Arnich, Nathalie, and Keck, Mathilde

Abstract

Brevetoxins (BTXs) constitute a family of lipid-soluble toxic cyclic polyethers mainly produced by Karenia brevis, which is the main vector for a foodborne syndrome known as neurotoxic shellfish poisoning (NSP) in humans. To prevent health risks associated with the consumption of contaminated shellfish in France, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) recommended assessing the effects of BTXs via an acute oral toxicity study in rodents. Here, we investigated the effect of a single oral administration in both male and female mice with several doses of BTX-3 (100 to 1,500 µg kg−1 bw) during a 48 h observation period in order to provide toxicity data to be used as a starting point for establishing an acute oral reference dose (ARfD). We monitored biological parameters and observed symptomatology, revealing different effects of this toxin depending on the sex. Females were more sensitive than males to the impact of BTX-3 at the lowest doses on weight loss. For both males and females, BTX-3 induced a rapid, transient and dose-dependent decrease in body temperature, and a transient dose-dependent reduced muscle activity. Males were more sensitive to BTX-3 than females with more frequent observations of failures in the grip test, convulsive jaw movements, and tremors. BTX-3's impacts on symptomatology were rapid, appearing during the 2 h after administration, and were transient, disappearing 24 h after administration. The highest dose of BTX-3 administered in this study, 1,500 µg kg−1 bw, was more toxic to males, leading to the euthanasia of three out of five males only 4 h after administration. BTX-3 had no effect on water intake, and affected neither the plasma chemistry parameters nor the organs' weight. We identified potential points of departure that could be used to establish an ARfD (decrease in body weight, body temperature, and muscle activity). [ABSTRACT FROM AUTHOR]

Published
2023
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18. One-year post-exposure assessment of 14C-few-layer graphene biodistribution in mice: single versus repeated intratracheal administration.

Author

Sallustrau, Antoine, Keck, Mathilde, Barbe, Peggy, Georgin, Dominique, Fresneau, Nathalie, Campidelli, Stephane, Pibaleau, Baptiste, Pinault, Mathieu, Mayne-L'Hermite, Martine, Granotier-Beckers, Christine, Schlegel, Michel, González, Viviana Jehová, Vázquez, Ester, Servent, Denis, and Taran, Frédéric

Published
2023
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19. One-year post-exposure assessment of 14C-few-layer graphene biodistribution in mice: single versus repeated intratracheal administration

Author

Sallustrau, Antoine, primary, Keck, Mathilde, additional, Barbe, Peggy, additional, Georgin, Dominique, additional, Fresneau, Nathalie, additional, Campidelli, Stephane, additional, Pibaleau, Baptiste, additional, Pinault, Mathieu, additional, Mayne-L'Hermite, Martine, additional, Granotier-Beckers, Christine, additional, Schlegel, Michel, additional, González Velázquez, Viviana Jehová, additional, Vázquez, Ester, additional, SERVENT, Denis, additional, and Taran, Frederic, additional

Published
2023
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20. From a Cone Snail Toxin to a Competitive MC4R Antagonist

Author

Reynaud, Steve, primary, Laurin, Suli-Anne, additional, Ciolek, Justyna, additional, Barbe, Peggy, additional, Van Baelen, Anne-Cécile, additional, Susset, Michaël, additional, Blondel, Florian, additional, Ghazarian, Marine, additional, Boeri, Julia, additional, Vanden Driessche, Margot, additional, Upert, Grégory, additional, Mourier, Gilles, additional, Kessler, Pascal, additional, Konnert, Laure, additional, Beroud, Rémy, additional, Keck, Mathilde, additional, Servent, Denis, additional, Bouvier, Michel, additional, and Gilles, Nicolas, additional

Published
2022
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21. LIT01-196, a Metabolically Stable Apelin-17 Analog, Normalizes Blood Pressure in Hypertensive DOCA-Salt Rats via a NO Synthase-dependent Mechanism

Author

Flahault, Adrien, Keck, Mathilde, Girault-Sotias, Pierre-Emmanuel, Esteoulle, Lucie, De Mota, Nadia, Bonnet, Dominique, Llorens-Cortes, Catherine, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Keck, Mathilde, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)

Subjects
[SDV]Life Sciences [q-bio], metabolically stable apelin analogs, RM1-950, DOCA-salt hypertensive rats, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, APJ, Hypertension, APJ receptor, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Apelin, Neurons and Cognition (q-bio.NC), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Therapeutics. Pharmacology, Metabolically stable apelin analog, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], DOCA-salt rat
Abstract

International audience; Apelin is a neuro-vasoactive peptide that plays a major role in the control of cardiovascular functions and water balance, but has an in-vivo half-life in the minute range, limiting its therapeutic use. We previously developed LIT01-196, a systemically active metabolically stable apelin-17 analog, produced by chemical addition of a fluorocarbon chain to the N-terminal part of apelin-17. LIT01-196 behaves as a potent full agonist for the apelin receptor and has an in vivo half-life in the bloodstream of 28 min after intravenous (i.v.) and 156 min after subcutaneous (s.c.) administrations in conscious normotensive rats. We aimed to investigate the effects of LIT01-196 following systemic administrations on arterial blood pressure, heart rate, fluid balance and electrolytes in conscious normotensive and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. Acute i.v. LIT01-196 administration, in increasing doses, dose-dependently decreases arterial blood pressure with ED 50 values of 9.8 and 3.1 nmol/kg in normotensive and hypertensive rats, respectively. This effect occurs for both via a nitric oxide-dependent mechanism. Moreover, acute s.c. LIT01-196 administration (90 nmol/kg) normalizes arterial blood pressure in conscious hypertensive DOCA-salt rats for more than 7 h. The LIT01-196-induced blood pressure decrease remains unchanged after 4 consecutive daily s.c. administrations of 90 nmol/kg, and does not induce any alteration of plasma sodium and potassium levels and kidney function as shown by the lack of change in plasma creatinine and urea nitrogen levels. Activating the apelin receptor with LIT01-196 may constitute a novel approach for the treatment of hypertension.

Published
2021
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22. Clinical and Genetic Spectrum of Bartter Syndrome Type 3

Author

Seys, Elsa, Andrini, Olga, Keck, Mathilde, Mansour-Hendili, Lamisse, Courand, Pierre-Yves, Simian, Christophe, Deschenes, Georges, Kwon, Theresa, Bertholet-Thomas, Aurélia, Bobrie, Guillaume, Borde, Jean Sébastien, Bourdat-Michel, Guylhène, Decramer, Stéphane, Cailliez, Mathilde, Krug, Pauline, Cozette, Paul, Delbet, Jean Daniel, Dubourg, Laurence, Chaveau, Dominique, Fila, Marc, Jourde-Chiche, Noémie, Knebelmann, Bertrand, Lavocat, Marie-Pierre, Lemoine, Sandrine, Djeddi, Djamal, Llanas, Brigitte, Louillet, Ferielle, Merieau, Elodie, Mileva, Maria, Mota-Vieira, Luisa, Mousson, Christiane, Nobili, François, Novo, Robert, Roussey-Kesler, Gwenaëlle, Vrillon, Isabelle, Walsh, Stephen B., Teulon, Jacques, Blanchard, Anne, and Vargas-Poussou, Rosa

Published
2017
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23. Monitoring In Vivo Performances of Protein–Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging

Author

Cahuzac, Héloïse, primary, Sallustrau, Antoine, additional, Malgorn, Carole, additional, Beau, Fabrice, additional, Barbe, Peggy, additional, Babin, Victor, additional, Dubois, Steven, additional, Palazzolo, Alberto, additional, Thai, Robert, additional, Correia, Isabelle, additional, Lee, Ki Baek, additional, Garcia-Argote, Sébastien, additional, Lequin, Olivier, additional, Keck, Mathilde, additional, Nozach, Hervé, additional, Feuillastre, Sophie, additional, Ge, Xin, additional, Pieters, Gregory, additional, Audisio, Davide, additional, and Devel, Laurent, additional

Published
2022
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25. Activating the apelin receptor with LIT01-196, a metabolically stable apelin analog, reverses AVP-induced antidiuresis and hyponatremia

Author

Flahault, Adrien, Girault-Sotias, Pierre-Emmanuel, Keck, Mathilde, Alvear-Perez, Rodrigo, De Mota, Nadia, Estéoulle, Lucie, Ramanoudjame, Sridévi, Iturrioz, Xavier, Bonnet, Dominique, Llorens-Cortes, Catherine, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Keck, Mathilde

Subjects
[SDV] Life Sciences [q-bio], [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV]Life Sciences [q-bio], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; Abstract Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

Published
2021
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26. A new Kunitz‐type snake toxin family associated with an original mode of interaction with the vasopressin 2 receptor

Author

Droctové, Laura, primary, Ciolek, Justyna, additional, Mendre, Christiane, additional, Chorfa, Amélia, additional, Huerta, Paola, additional, Carvalho, Chrystelle, additional, Gouin, Charlotte, additional, Lancien, Manon, additional, Stanajic‐Petrovic, Goran, additional, Braco, Lorine, additional, Blanchet, Guillaume, additional, Upert, Gregory, additional, De Pauw, Gregory, additional, Barbe, Peggy, additional, Keck, Mathilde, additional, Mourier, Gilles, additional, Mouillac, Bernard, additional, Denis, Servent, additional, Rodríguez de la Vega, Ricardo C., additional, Quinton, Loïc, additional, and Gilles, Nicolas, additional

Published
2022
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28. First evidence that emerging pinnatoxin-G, a contaminant of shellfish, reaches the brain and crosses the placental barrier

Author

Servent, Denis, Malgorn, Carole, Bernes, Mylène, Gil, Sophie, Simasotchi, Christelle, Hérard, Anne-Sophie, Delzescaux, Thierry, Thai, Robert, Barbe, Peggy, Keck, Mathilde, Beau, Fabrice, Zakarian, Armen, Dive, Vincent, Molgó, Jordi, Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), University of California [Santa Barbara] (UC Santa Barbara), University of California (UC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of California [Santa Barbara] (UCSB), University of California, and Keck, Mathilde

Subjects
[SDE] Environmental Sciences, [SDV.TOX.ECO] Life Sciences [q-bio]/Toxicology/Ecotoxicology, Placenta, Brain, Rats, Seafood, Pregnancy, [SDE]Environmental Sciences, Animals, Humans, Female, Tissue Distribution, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, Shellfish
Abstract

International audience; Massive proliferation of some toxic marine dinoflagellates is responsible for the occurrence of harmful algal blooms and the contamination of fish and shellfish worldwide. Pinnatoxins (PnTx) (A-H) comprise an emerging phycotoxin family belonging to the cyclic imine toxin group. Interest has been focused on these lipophilic, fast-acting and highly potent toxins because they are widely found in contaminated shellfish, and can represent a risk for seafood consumers. PnTx display a potent antagonist effect on nicotinic acetylcholine receptors (nAChR), and in this study we assessed in vivo the ability of PnTx-G to cross physiological barriers to reach its molecular target. Radiolabeled [3H]-PnTx-G synthesized with good radiochemical purity and yield retained the high affinity of the natural toxin. Oral gavage or intravenous administration to adult rats and digital autoradiographic analyses revealed the biodistribution and toxicokinetics of [3H]-PnTx-G, which is rapidly cleared from blood, and accumulates in the liver and small intestine. The labeling of peripheral and brain adult/embryo rat tissues highlights its ability to cross the intestinal, blood-brain and placental barriers. High-resolution 3D-imaging and in vitro competition studies on rat embryo sections revealed the specificity of [3H]-PnTx-G binding and its selectivity for muscle and neuronal nAChR subtypes (such as α7 subtype). The use of a human perfused cotyledon model and mass spectrometry analyses disclosed that PnTx-G crosses the human placental barrier. The increasing worldwide occurrence of both the dinoflagellate Vulcanodinium rugosum and PnTx-contaminated shellfish, due to climate warming, raises concerns about the potential adverse impact that exposure to pinnatoxins may have for human health.

Published
2020
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29. Emergence of Orai3 activity during cardiac hypertrophy

Author

Saliba, Youakim, Keck, Mathilde, Marchand, Alexandre, Atassi, Fabrice, Ouillé, Aude, Cazorla, Olivier, Trebak, Mohamed, Pavoine, Catherine, Lacampagne, Alain, Hulot, Jean-Sébastien, Farès, Nassim, Fauconnier, Jérémy, and Lompré, Anne-Marie

Published
2015
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30. A screening pipeline identifies a broad-spectrum inhibitor of bacterial AB toxins with cross protection against influenza A virus H1N1 and SARS-CoV-2

Author

Wu, Yu, primary, Mahtal, Nassim, additional, Swistak, Léa, additional, Sagadiev, Sara, additional, Acharya, Mridu, additional, Demeret, Caroline, additional, van der Werf, Sylvie, additional, Guivel-Benhassine, Florence, additional, Schwartz, Olivier, additional, Petracchini, Serena, additional, Mettouchi, Amel, additional, Paillares, Eléa, additional, Caramelle, Lucie, additional, Couvineau, Pierre, additional, Thai, Robert, additional, Barbe, Peggy, additional, Keck, Mathilde, additional, Brodin, Priscille, additional, Machelart, Arnaud, additional, Sencio, Valentin, additional, Trottein, François, additional, Sachse, Martin, additional, Chicanne, Gaëtan, additional, Payrastre, Bernard, additional, Ville, Florian, additional, Kreis, Victor, additional, Popoff, Michel-Robert, additional, Johannes, Ludger, additional, Cintrat, Jean-Christophe, additional, Barbier, Julien, additional, Gillet, Daniel, additional, and Lemichez, Emmanuel, additional

Published
2021
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31. A new Kunitz-type snake toxin family associated with an original mode of interaction with the vasopressin 2 receptor.

Author

Droctové, Laura, primary, CioleK, Justyna, additional, Mendre, Christiane, additional, Chorfa, Amélia, additional, Huerta, Paola, additional, Carvalho, Chrystelle, additional, Gouin, Charlotte, additional, Lancien, Manon, additional, Blanchet, Guillaume, additional, Upert, Gregory, additional, Pauw, Edwin De, additional, Barbe, Peggy, additional, Keck, Mathilde, additional, Mourier, Gilles, additional, Mouillac, Bernard, additional, Servent, Denis, additional, Rodriguez-de-la-vega, Ricardo, additional, Quinton, Loïc, additional, and Gilles, Nicolas, additional

Published
2021
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32. A variant of ASIC2 mediates sodium retention in nephrotic syndrome

Author

Fila, Marc, primary, Sassi, Ali, additional, Brideau, Gaelle, additional, Cheval, Lydie, additional, Morla, Luciana, additional, Houillier, Pascal, additional, Walter, Christine, additional, Gennaoui, Michel, additional, Collignon, Laure, additional, Keck, Mathilde, additional, Planelles, Gabrielle, additional, Bakouh, Naziha, additional, Peuchmaur, Michel, additional, Deschenes, Georges, additional, Anegon, Ignacio, additional, Remy, Séverine, additional, Vogt, Bruno, additional, Crambert, Gilles, additional, and Doucet, Alain, additional

Published
2021
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34. A new variant of ASIC2 mediates sodium retention in nephrotic syndrome

Author

Fila, Marc, primary, Sassi, Ali, additional, Brideau, Gaëlle, additional, Cheval, Lydie, additional, Morla, Luciana, additional, Houillier, Pascal, additional, Walter, Christine, additional, Gennaoui, Michel, additional, Collignon L, Laure, additional, Keck, Mathilde, additional, Planelles, Gabrielle, additional, Bakouh, Naziha, additional, Peuchmaur, Michel, additional, Deschênes, Georges, additional, Anegon, Ignacio, additional, Remy, Séverine, additional, Vogt, Bruno, additional, Crambert, Gilles, additional, and Doucet, Alain, additional

Published
2021
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38. Analysis of CLCNKB mutations at dimer‐interface, calcium‐binding site, and pore reveals a variety of functional alterations in ClC‐Kb channel leading to Bartter syndrome

Author

Bignon, Yohan, primary, Sakhi, Imene, additional, Bitam, Sara, additional, Bakouh, Naziha, additional, Keck, Mathilde, additional, Frachon, Nadia, additional, Paulais, Marc, additional, Planelles, Gabrielle, additional, Teulon, Jacques, additional, and Andrini, Olga, additional

Published
2019
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39. Analysis of CLCNKB mutations at dimer‐interface, calcium‐binding site, and pore reveals a variety of functional alterations in ClC‐Kb channel leading to Bartter syndrome.

Author

Bignon, Yohan, Sakhi, Imene, Bitam, Sara, Bakouh, Naziha, Keck, Mathilde, Frachon, Nadia, Paulais, Marc, Planelles, Gabrielle, Teulon, Jacques, and Andrini, Olga

Abstract

Pathological missense mutations in CLCNKB gene give a wide spectrum of clinical phenotypes in Bartter syndrome type III patients. Molecular analysis of the mutated ClC‐Kb channels can be helpful to classify the mutations according to their functional alteration. We investigated the functional consequences of nine mutations in the CLCNKB gene causing Bartter syndrome. We first established that all tested mutations lead to decreased ClC‐Kb currents. Combining electrophysiological and biochemical methods in Xenopus laevis oocytes and in MDCKII cells, we identified three classes of mutations. One class is characterized by altered channel trafficking. p.A210V, p.P216L, p.G424R, and p.G437R are totally or partially retained in the endoplasmic reticulum. p.S218N is characterized by reduced channel insertion at the plasma membrane and altered pH‐sensitivity; thus, it falls in the second class of mutations. Finally, we found a novel class of functionally inactivated mutants normally present at the plasma membrane. Indeed, we found that p.A204T alters the pH‐sensitivity, p.A254V abolishes the calcium‐sensitivity. p.G219C and p.G465R are probably partially inactive at the plasma membrane. In conclusion, most pathogenic mutants accumulate partly or totally in intracellular compartments, but some mutants are normally present at the membrane surface and simultaneously show a large range of altered channel gating properties. [ABSTRACT FROM AUTHOR]

Published
2020
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40. MQ232, A Snake Toxin Derivative for Treatment of Hyponatremia and Polycystic Kidney Diseases

Author

Stanajic-Petrovic, Goran, Keck, Mathilde, Barbe, Peggy, Urman, Apolline, Correia, Evelyne, Isnard, Pierre, Duong Van Huyen, Jean-Paul, Chmeis, Khawla, Diarra, Sékou Siramakan, Palea, Stefano, Theodoro, Frederic, Nguyen, Anvi-Laëtitia, Castelli, Florence, Pruvost, Alain, Zhao, Wenchao, Mendre, Christiane, Mouillac, Bernard, Bienaimé, Frank, Robin, Philippe, Kessler, Pascal, Llorens-Cortes, Catherine, Servent, Denis, Nozach, Hervé, Maillère, Bernard, Guo, Dong, Truillet, Charles, and Gilles, Nicolas

Published
2024
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41. Novel CLCNKB mutations causing Bartter syndrome affect channel surface expression Human Mutation

Author

Keck, Mathilde, Andrini, Olga, Lahuna, Olivier, Burgos, Johanna, Cid, L Pablo, Sepúlveda, Francisco, L'Hoste, Sébastien, Blanchard, Anne, Vargas-Poussou, Rosa, Lourdel, Stéphane, Teulon, Jacques, Cid, L. Pablo, L‘Hoste, Sébastien, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), 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), Centro de Estudios Científicos (CECs), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft, Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Évolution, Écologie et Paléontologie (Evo-Eco-Paleo) - UMR 8198 (Evo-Eco-Paléo), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR Odontologie, Université de Nantes (UN), 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), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, University of California [San Diego] (UC San Diego), University of California, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Physiologie [Georges-Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Paris - Faculté de Médecine Paris Centre (UP Médecine Paris Centre), Centro de Estudios Científicos, Valdivia, Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
chloride channel, Patch-Clamp Techniques, outer medullary collecting duct, [SDV]Life Sciences [q-bio], NPPB, CLCNKB, 2′-stilbene disulfonic acid disodium salt, MESH: Recombinant Proteins, ClC family, 4′-diisothiocyanato-2, MESH: Syndrome, MESH: Animals, ClC familly, ComputingMilieux_MISCELLANEOUS, ClC-K1, distal convoluted tubule, DCT, DPC, Hydrogen-Ion Concentration, Middle Aged, MESH: Infant, DIDS, Phenotype, MESH: Young Adult, MESH: HEK293 Cells, MESH: Kidney Tubules, Female, 5-nitro-2-(3-phenylpropylamino) benzoic acid, connecting tubule, OMCD, Adult, kidney, CNT, Bartter, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, CLCNKB, ClC family, Bartter, 2-(phenylamino) benzoic acid, 4′-diisothiocyanato-2, 2′-stilbene disulfonic acid disodium salt, 5-nitro-2-(3-phenylpropylamino) benzoic acid, CCD, CNT, CTAL, Chloride channel, ClC, ClC-K, ClC-K1, DCT, DIDS, DPC, Kidney, NPPB, OMCD, Patch-clamp, connecting tubule, cortical collecting duct, cortical thick ascending limb, distal convoluted tubule, kidney chloride channel, outer medullary collecting duct, cortical collecting duct, MESH: Oocytes, Young Adult, Chloride Channels, CTAL, MESH: Xenopus laevis, ClC, MESH: Patch-Clamp Techniques, Humans, Point Mutation, CCD, MESH: Point Mutation, MESH: Humans, MESH: Chloride Channels, Bartter Syndrome, MESH: Male, cortical thick ascending limb, Mutation, Calcium, MESH: Sodium Potassium Chloride Symporter Inhibitors, kidney chloride channel, 2-(phenylamino) benzoic acid, Patch-clamp, ClC-K
Abstract

International audience; ClC-Kb, a member of the ClC family of Cl(-) channels/transporters, plays a major role in the absorption of NaCl in the distal nephron. CLCNKB mutations cause Bartter syndrome type 3, a hereditary renal salt-wasting tubulopathy. Here, we investigate the functional consequences of a Val to Met substitution at position 170 (V170M, α helix F), which was detected in eight patients displaying a mild phenotype. Conductance and surface expression were reduced by ~40-50 %. The regulation of channel activity by external H(+) and Ca(2+) is a characteristic property of ClC-Kb. Inhibition by external H(+) was dramatically altered, with pKH shifting from 7.6 to 6.0. Stimulation by external Ca(2+) on the other hand was no longer detectable at pH 7.4, but was still present at acidic pH values. Functionally, these regulatory modifications partly counterbalance the reduced surface expression by rendering V170M hyperactive. Pathogenic Met170 seems to interact with another methionine on α helix H (Met227) since diverse mutations at this site partly removed pH sensitivity alterations of V170M ClC-Kb. Exploring other disease-associated mutations, we found that a Pro to Leu substitution at position 124 (α helix D, Simon et al., Nat Genet 1997, 17:171-178) had functional consequences similar to those of V170M. In conclusion, we report here for the first time that ClC-Kb disease-causing mutations located around the selectivity filter can result in both reduced surface expression and hyperactivity in heterologous expression systems. This interplay must be considered when analyzing the mild phenotype of patients with type 3 Bartter syndrome.

Published
2014
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42. The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron

Author

Hennings, J. Christopher, primary, Andrini, Olga, additional, Picard, Nicolas, additional, Paulais, Marc, additional, Huebner, Antje K., additional, Cayuqueo, Irma Karen Lopez, additional, Bignon, Yohan, additional, Keck, Mathilde, additional, Cornière, Nicolas, additional, Böhm, David, additional, Jentsch, Thomas J., additional, Chambrey, Régine, additional, Teulon, Jacques, additional, Hübner, Christian A., additional, and Eladari, Dominique, additional

Published
2016
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43. Functional analysis of novel CLC-KB mutations causing Bartter syndrome

Author

Keck, Mathilde, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris VI, Jacques Teulon, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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)-Centre National de la Recherche Scientifique (CNRS), and Bupmc, Theses

Subjects
tubule distal, électrophysiologie, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], luminescence, syndrome de Bartter, CLC-KB, mutations pathogènes
Abstract

Bartter's syndrome type III results from loss-of-function mutations in the CLCNKB gene that encodes the CLC-KB chloride channel. To date, few CLCNKB mutations have been fully functionally investigated. In this study, we have investigated the functional consequences of novel CLCNKB mutations (collected by the Department of Genetics of the European Georges Pompidou Hospital) in Xenopus laevis oocytes, HEK293T and MDCK cells, in terms of electrical activity and surface expression. We have demonstrated that all mutations decreased plasma membrane expression and conductance of CLC-KB in similar proportions, indicating that altered cell surface expression is the main functional defect caused by CLCNKB mutations. However, some mutations also alter external pH and calcium sensitivity. The physiological relevance of these regulations is open to question, but clearly, their alteration could have a pathological impact. In conclusion, this functional study highlights the essential role of CLC-KB in the preservation of sodium balance and provides new clues for finding specific therapeutic drugs that would be able to restore sufficient function of CLC-KB in patients with Bartter's syndrome type III. Moreover, functional analysis of mutations is an extremely powerful tool for structure-function studies. In association with the search of new partners, it should allow discovering the physiological regulations of this channel that are almost unknown., Le syndrome de Bartter de type III résulte de mutations du gène CLCNKB codant le canal chlorure CLC-KB. Un grand nombre de mutations a été répertorié, mais peu d'entre elles ont été caractérisées fonctionnellement. Devant ce manque de données, nous nous sommes fixés comme objectif de procéder à une analyse fonctionnelle des mutations de CLCNKB pour tenter d'approfondir davantage les mécanismes de régulation de CLC-KB. Ce travail a nécessité l'emploi de trois systèmes d'expression hétérologue, les ovocytes de Xenopus laevis et les lignées cellulaires rénales HEK293T et MDCK, afin de procéder à des analyses électrophysiologiques et des expériences de biologie cellulaire. Nous démontrons que toutes les mutations étudiées altèrent l'expression membranaire de la protéine et que la conductance résiduelle est proportionnée à cette expression. Ainsi, la réduction des courants provient d'une réduction du nombre de canaux et non d'une altération majeure de la conduction ou de la régulation. Nous rapportons également que certaines mutations modifient la sensibilité au pH et au calcium extracellulaires du CLC-KB. Cette altération peut avoir un impact pathologique majeur. En conclusion, cette étude fonctionnelle montre le rôle essentiel du CLC-KB dans le maintien de la balance sodée et laisse entrevoir un espoir thérapeutique à long terme de restauration des anomalies précisément identifiées. Enfin, l'analyse de mutations est un outil extrêmement puissant pour les études structure-fonction. Associée à la recherche de nouveaux partenaires, elle devrait permettre de découvrir les régulations physiologiques de ce canal, pour l'heure presqu'inconnues.

Published
2012

46. Emergence of Orai3 activity during cardiac hypertrophy

Author

Saliba, Youakim, primary, Keck, Mathilde, additional, Marchand, Alexandre, additional, Atassi, Fabrice, additional, Ouillé, Aude, additional, Cazorla, Olivier, additional, Trebak, Mohamed, additional, Pavoine, Catherine, additional, Lacampagne, Alain, additional, Hulot, Jean-Sébastien, additional, Farès, Nassim, additional, Fauconnier, Jérémy, additional, and Lompré, Anne-Marie, additional

Published
2014
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47. CLCNKB mutations causing mild Bartter syndrome profoundly alter the pH and Ca2+ dependence of ClC-Kb channels

Author

Andrini, Olga, primary, Keck, Mathilde, additional, L’Hoste, Sébastien, additional, Briones, Rodolfo, additional, Mansour-Hendili, Lamisse, additional, Grand, Teddy, additional, Sepúlveda, Francisco V., additional, Blanchard, Anne, additional, Lourdel, Stéphane, additional, Vargas-Poussou, Rosa, additional, and Teulon, Jacques, additional

Published
2013
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48. Characterization of the mouse ClC-K1/Barttin chloride channel

Author

L'Hoste, Sébastien, primary, Diakov, Alexei, additional, Andrini, Olga, additional, Genete, Mathieu, additional, Pinelli, Laurent, additional, Grand, Teddy, additional, Keck, Mathilde, additional, Paulais, Marc, additional, Beck, Laurent, additional, Korbmacher, Christoph, additional, Teulon, Jacques, additional, and Lourdel, Stéphane, additional

Published
2013
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49. Mutations in SLC2A2 Gene Reveal hGLUT2 Function in Pancreatic β Cell Development

Author

Michau, Aurélien, primary, Guillemain, Ghislaine, additional, Grosfeld, Alexandra, additional, Vuillaumier-Barrot, Sandrine, additional, Grand, Teddy, additional, Keck, Mathilde, additional, L'Hoste, Sébastien, additional, Chateau, Danielle, additional, Serradas, Patricia, additional, Teulon, Jacques, additional, De Lonlay, Pascale, additional, Scharfmann, Raphaël, additional, Brot-Laroche, Edith, additional, Leturque, Armelle, additional, and Le Gall, Maude, additional

Published
2013
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