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3. A mutation of the human EPHB2 gene leads to a major platelet functional defect

Author

Berrou, Eliane, Soukaseum, Christelle, Favier, Rémi, Adam, Frédéric, Elaib, Ziane, Kauskot, Alexandre, Bordet, Jean-Claude, Ballerini, Paola, Loyau, Stephane, Feng, Miao, Dias, Karine, Muheidli, Abbas, Girault, Stephane, Nurden, Alan T., Turro, Ernest, Ouwehand, Willem H., Denis, Cécile V., Jandrot-Perrus, Martine, Rosa, Jean-Philippe, Nurden, Paquita, and Bryckaert, Marijke

Published
2018
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5. Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence

Author

Dupont, Annabelle, Soukaseum, Christelle, Cheptou, Mathilde, Adam, Frédéric, Nipoti, Thomas, Lourenco-Rodrigues, Marc-Damien, Legendre, Paulette, Proulle, Valérie, Rauch, Antoine, Kawecki, Charlotte, Bryckaert, Marijke, Rosa, Jean-Philippe, Paris, Camille, Ternisien, Catherine, Boisseau, Pierre, Goudemand, Jenny, Borgel, Delphine, Lasne, Dominique, Maurice, Pascal, Lenting, Peter J., Denis, Cécile V., Susen, Sophie, Kauskot, Alexandre, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University College Cork (UCC), Hémostase et biologie vasculaire, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémostase et thrombose, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Lille 2 - Faculté de Médecine, Department of Hematology [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie, PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), 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 Centre National de la Recherche Scientifique (CNRS)-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 - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Blood Platelets, Male, Platelet Count, [SDV]Life Sciences [q-bio], Integrin beta3, von Willebrand Disease, Type 2, Prognosis, Thrombocytopenia, Article, N-Acetylneuraminic Acid, Platelet Biology & its Disorders, Mice, Polysaccharides, hemic and lymphatic diseases, Case-Control Studies, Mutation, von Willebrand Factor, Animals, Humans, Female, Integrin alpha2beta1, Protein Processing, Post-Translational, ComputingMilieux_MISCELLANEOUS, Follow-Up Studies
Abstract

Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo. The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro, we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified αIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo. In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia.

Published
2019

6. A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis

Author

López-Cayuqueo, Karen I., primary, Chavez-Canales, Maria, additional, Pillot, Alexia, additional, Houillier, Pascal, additional, Jayat, Maximilien, additional, Baraka-Vidot, Jennifer, additional, Trepiccione, Francesco, additional, Baudrie, Véronique, additional, Büsst, Cara, additional, Soukaseum, Christelle, additional, Kumai, Yusuke, additional, Jeunemaître, Xavier, additional, Hadchouel, Juliette, additional, Eladari, Dominique, additional, and Chambrey, Régine, additional

Published
2018
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8. Acute genetic ablation of pendrin lowers blood pressure in mice

Author

Trepiccione, Francesco, primary, Soukaseum, Christelle, additional, Baudrie, Veronique, additional, Kumai, Yusuke, additional, Teulon, Jacques, additional, Villoutreix, Bruno, additional, Cornière, Nicolas, additional, Wangemann, Philine, additional, Griffith, Andrew J., additional, Byung Choi, Yoon, additional, Hadchouel, Juliette, additional, Chambrey, Regine, additional, and Eladari, Dominique, additional

Published
2017
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10. LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

Author

Kauskot, Alexandre, primary, Poirault-Chassac, Sonia, additional, Adam, Frédéric, additional, Muczynski, Vincent, additional, Aymé, Gabriel, additional, Casari, Caterina, additional, Bordet, Jean-Claude, additional, Soukaseum, Christelle, additional, Rothschild, Chantal, additional, Proulle, Valérie, additional, Pietrzyk-Nivau, Audrey, additional, Berrou, Eliane, additional, Christophe, Olivier D., additional, Rosa, Jean-Philippe, additional, Lenting, Peter J., additional, Bryckaert, Marijke, additional, Denis, Cécile V., additional, and Baruch, Dominique, additional

Published
2016
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11. A mutation of the human EPHB2gene leads to a major platelet functional defect

Author

Berrou, Eliane, Soukaseum, Christelle, Favier, Rémi, Adam, Frédéric, Elaib, Ziane, Kauskot, Alexandre, Bordet, Jean-Claude, Ballerini, Paola, Loyau, Stephane, Feng, Miao, Dias, Karine, Muheidli, Abbas, Girault, Stephane, Nurden, Alan T., Turro, Ernest, Ouwehand, Willem H., Denis, Cécile V., Jandrot-Perrus, Martine, Rosa, Jean-Philippe, Nurden, Paquita, and Bryckaert, Marijke

Abstract

The ephrin transmembrane receptor family of tyrosine kinases is involved in platelet function. We report the first EPHB2variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts. Whole-exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2gene. P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous. The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbβ3 activation, and granule secretion induced by G-protein–coupled receptor (GPCR) agonists and convulxin, as well as in thrombus formation on collagen under flow. In contrast, clot retraction, flow-dependent platelet adhesion, and spreading on fibrinogen were only mildly affected, indicating limited effects on αIIbβ3 outside-in signaling. Most importantly, Lyn, Syk, and FcRγ phosphorylation, the initial steps in glycoprotein VI (GPVI) platelet signaling were drastically impaired in the absence of platelet–platelet contact, indicating a positive role for EPHB2 in GPVI activation. Likewise platelet activation by PAR4-AP showed defective Src activation, as opposed to normal protein kinase C activity and Ca2+mobilization. Overexpression of wild-type and R745C EPHB2 variant in RBL-2H3 (rat basophilic leukemia) cells stably expressing human GPVI confirmed that EPHB2 R745C mutation impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with EPHB2-ephrin–mediated cell-to-cell contact. In conclusion, this novel inherited platelet disorder affecting EPHB2 demonstrates this tyrosine kinase receptor plays an important role in platelet function through crosstalk with GPVI and GPCR signaling.

Published
2018
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12. WNK-SPAK-NCC Cascade Revisited

Author

Chávez-Canales, María, primary, Zhang, Chong, additional, Soukaseum, Christelle, additional, Moreno, Erika, additional, Pacheco-Alvarez, Diana, additional, Vidal-Petiot, Emmanuelle, additional, Castañeda-Bueno, María, additional, Vázquez, Norma, additional, Rojas-Vega, Lorena, additional, Meermeier, Nicholas P., additional, Rogers, Shaunessy, additional, Jeunemaitre, Xavier, additional, Yang, Chao-Ling, additional, Ellison, David H., additional, Gamba, Gerardo, additional, and Hadchouel, Juliette, additional

Published
2014
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13. A fate-mapping approach reveals the composite origin of the connecting tubule and alerts on "single-cell"-specific KO model of the distal nephron.

Author

Trepiccione, Francesco, Soukaseum, Christelle, Iervolino, Anna, Petrillo, Federica, Zacchia, Miriam, Schutz, Gunther, Eladari, Dominique, Capasso, Giovambattista, and Hadchouel, Juliette

Subjects
*KIDNEY tubules, *FATE mapping (Genetics), *HOMEOSTASIS, *PHYSIOLOGY
Abstract

The distal nephron is a heterogeneous part of the nephron composed by six different cell types, forming the epithelium of the distal convoluted (DCT), connecting, and collecting duct. To dissect the function of these cells, knockout models specific for their unique cell marker have been created. However, since this part of the nephron develops at the border between the ureteric bud and the metanephric mesenchyme, the specificity of the single cell markers has been recently questioned. Here, by mapping the fate of the aquaporin 2 (AQP2) and Na+-Cl- cotransporter (NCC)-positive cells using transgenic mouse lines expressing the yellow fluorescent protein fluorescent marker, we showed that the origin of the distal nephron is extremely composite. Indeed, AQP2-expressing precursor results give rise not only to the principal cells, but also to some of the A- and B-type intercalated cells and even to cells of the DCT. On the other hand, some principal cells and B-type intercalated cells can develop from NCC-expressing precursors. In conclusion, these results demonstrate that the origin of different cell types in the distal nephron is not as clearly defined as originally thought. Importantly, they highlight the fact that knocking out a gene encoding for a selective functional marker in the adult does not guarantee cell specificity during the overall kidney development. Tools allowing not only cell-specific but also time-controlled recombination will be useful in this sense. [ABSTRACT FROM AUTHOR]

Published
2016
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14. A fate-mapping approach reveals the composite origin of the connecting tubule and alerts on 'single-cell'-specific KO model of the distal nephron

Author

Anna Iervolino, Federica Petrillo, Günther Schütz, Juliette Hadchouel, Francesco Trepiccione, Giovambattista Capasso, Christelle Soukaseum, Dominique Eladari, Miriam Zacchia, Trepiccione, Francesco, Soukaseum, Christelle, Iervolino, Anna, Petrillo, Federica, Zacchia, Miriam, Schütz, Gunther, Eladari, Dominique, Capasso, Giovambattista, and Hadchouel, Juliette

Subjects
0301 basic medicine, Cell type, Physiology, Mice, Transgenic, Nephron, Biology, Models, Biological, Distal nephron, Mice, 03 medical and health sciences, Fate mapping, medicine, Animals, Connecting tubule, Kidney Tubules, Collecting, Kidney Tubules, Distal, NCC, Aquaporin 2, urogenital system, Nephrons, Anatomy, AQP2, Sodium Chloride Symporters, Epithelium, 030104 developmental biology, medicine.anatomical_structure, Duct (anatomy)
Abstract

The distal nephron is a heterogeneous part of the nephron composed by six different cell types, forming the epithelium of the distal convoluted (DCT), connecting, and collecting duct. To dissect the function of these cells, knockout models specific for their unique cell marker have been created. However, since this part of the nephron develops at the border between the ureteric bud and the metanephric mesenchyme, the specificity of the single cell markers has been recently questioned. Here, by mapping the fate of the aquaporin 2 (AQP2) and Na+-Cl−cotransporter (NCC)-positive cells using transgenic mouse lines expressing the yellow fluorescent protein fluorescent marker, we showed that the origin of the distal nephron is extremely composite. Indeed, AQP2-expressing precursor results give rise not only to the principal cells, but also to some of the A- and B-type intercalated cells and even to cells of the DCT. On the other hand, some principal cells and B-type intercalated cells can develop from NCC-expressing precursors. In conclusion, these results demonstrate that the origin of different cell types in the distal nephron is not as clearly defined as originally thought. Importantly, they highlight the fact that knocking out a gene encoding for a selective functional marker in the adult does not guarantee cell specificity during the overall kidney development. Tools allowing not only cell-specific but also time-controlled recombination will be useful in this sense.

Published
2016

15. A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis

Author

Jennifer Baraka-Vidot, María Chávez-Canales, Régine Chambrey, Juliette Hadchouel, Alexia Pillot, Maximilien Jayat, Yusuke Kumai, Karen I. López-Cayuqueo, Christelle Soukaseum, Dominique Eladari, Xavier Jeunemaitre, Francesco Trepiccione, Véronique Baudrie, Cara Büsst, Pascal Houillier, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), 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), Unité des maladies rénales et métaboliques [Hôpital Européen Georges-Pompidou - APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), 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), 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), Groupe d'Etude sur l'Inflammation Chronique et l'Obésité (GEICO), Université de La Réunion (UR), University of Edinburgh, López-Cayuqueo, Karen I, Chavez-Canales, Maria, Pillot, Alexia, Houillier, Pascal, Jayat, Maximilien, Baraka-Vidot, Jennifer, Trepiccione, Francesco, Baudrie, Véronique, Büsst, Cara, Soukaseum, Christelle, Kumai, Yusuke, Jeunemaître, Xavier, Hadchouel, Juliette, Eladari, Dominique, Chambrey, Régine, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and 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)

Subjects
0301 basic medicine, Male, pendrin, Pseudohypoaldosteronism, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Sodium Chloride, Renal tubular acidosis, Gene Knockout Techniques, Mice, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, biology, Chemistry, Reabsorption, Acidosis, Renal Tubular, WNK4, Up-Regulation, medicine.anatomical_structure, Nephrology, Sulfate Transporters, renal tubular acidosi, medicine.medical_specialty, hypertension, Mutation, Missense, Mice, Transgenic, Protein Serine-Threonine Kinases, 03 medical and health sciences, intercalated cell, Internal medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Distal convoluted tubule, Kidney Tubules, Collecting, Sodium-Bicarbonate Symporters, Metabolic acidosis, Pendrin, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Renal Elimination, 030104 developmental biology, Endocrinology, Gordon syndrome, biology.protein, Potassium, familial hyperkalemic hypertension, Homeostasis
Abstract

Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in the WNK1, WNK4, KLHL3 or CUL3 gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in β-intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis. Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in the WNK1, WNK4, KLHL3 or CUL3 gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in beta-intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis.

Published
2018

16. Acute genetic ablation of pendrin lowers blood pressure in mice

Author

Philine Wangemann, Régine Chambrey, Dominique Eladari, Francesco Trepiccione, Véronique Baudrie, Jacques Teulon, Juliette Hadchouel, Andrew J. Griffith, Bruno O. Villoutreix, Yoon Byung Choi, Christelle Soukaseum, Nicolas Cornière, Yusuke Kumai, Trepiccione, Francesco, Soukaseum, Christelle, Baudrie, Veronique, Kumai, Yusuke, Teulon, Jacque, Villoutreix, Bruno, Cornière, Nicola, Wangemann, Philine, Griffith, Andrew J, Byung Choi, Yoon, Hadchouel, Juliette, Chambrey, Regine, Eladari, Dominique, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Molécules Thérapeutiques in silico (MTI), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Kansas State University, and National Institutes of Health [Bethesda] (NIH)

Subjects
Male, Genetically modified mouse, medicine.medical_specialty, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Anion Transport Proteins, 030232 urology & nephrology, Blood Pressure, Mice, Transgenic, 030204 cardiovascular system & hematology, Chloride, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Internal medicine, Extracellular fluid, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, otorhinolaryngologic diseases, Animals, Diuretic, Pendrin, Transplantation, Kidney, biology, business.industry, Reabsorption, Original Articles, diuretics, Connecting tubule, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Endocrinology, Blood pressure, medicine.anatomical_structure, Sulfate Transporters, Nephrology, intercalated cells, Hypertension, biology.protein, business, Intercalated cell
Abstract

International audience; Background: Pendrin, the chloride/bicarbonate exchanger of β-intercalated cells of the renal connecting tubule and the collecting duct, plays a key role in NaCl reabsorption by the distal nephron. Therefore, pendrin may be important for the control of extracellular fluid volume and blood pressure.Methods: Here, we have used a genetic mouse model in which the expression of pendrin can be switched-on in vivo by the administration of doxycycline. Pendrin can also be rapidly removed when doxycycline administration is discontinued. Therefore, our genetic strategy allows us to test selectively the acute effects of loss of pendrin function.Results: We show that acute loss of pendrin leads to a significant decrease of blood pressure. In addition, acute ablation of pendrin did not alter significantly the acid-base status or blood K + concentration.Conclusion: By using a transgenic mouse model, avoiding off-target effects related to pharmacological compounds, this study suggests that pendrin could be a novel target to treat hypertension.

Published
2017

17. Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence.

Author

Dupont A, Soukaseum C, Cheptou M, Adam F, Nipoti T, Lourenco-Rodrigues MD, Legendre P, Proulle V, Rauch A, Kawecki C, Bryckaert M, Rosa JP, Paris C, Ternisien C, Boisseau P, Goudemand J, Borgel D, Lasne D, Maurice P, Lenting PJ, Denis CV, Susen S, and Kauskot A

Subjects
Animals, Blood Platelets metabolism, Case-Control Studies, Female, Follow-Up Studies, Humans, Integrin alpha2beta1 metabolism, Integrin beta3 metabolism, Male, Mice, N-Acetylneuraminic Acid metabolism, Platelet Count, Polysaccharides metabolism, Prognosis, Protein Processing, Post-Translational, Thrombocytopenia etiology, Thrombocytopenia metabolism, von Willebrand Disease, Type 2 genetics, von Willebrand Disease, Type 2 pathology, Blood Platelets pathology, Mutation, N-Acetylneuraminic Acid chemistry, Thrombocytopenia pathology, von Willebrand Disease, Type 2 complications, von Willebrand Factor genetics
Abstract

Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro , we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified αIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia., (Copyright© 2019 Ferrata Storti Foundation.)

Published
2019
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