17 results on '"Canonica J"'
Search Results
2. CFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex
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Borras, C., Canonica, J., Jorieux, S., Abache, T., El Sanharawi, M., Klein, C., Delaunay, K., Jonet, L., Salvodelli, M., Naud, M.C., Arsenijevic, Y., Shalabi, A., Souchaud, L., Behar-Cohen, F., Dinet, V., 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 de Paris (UP), Sorbonne Université (SU), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Université de Lausanne (UNIL), Universitätsklinikum Frankfurt, 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), Laboratoire Français du fractionnement et des Biotechnologies, Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, Développement, vieillissement et pathologie de la rétine, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Maladies Oculaires : Innovations Therapeutiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Retinal Degeneration and Regeneration, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Laboratoire Français du Fractionnement et des Biotechnologies, and affiliation inconnue more...
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[SDV]Life Sciences [q-bio] ,Blotting, Western ,Induced Pluripotent Stem Cells ,lcsh:Medicine ,Apoptosis ,Complement Membrane Attack Complex ,Retinal Pigment Epithelium ,Real-Time Polymerase Chain Reaction ,Article ,Cell Line ,Tight Junctions ,Microscopy, Electron, Transmission ,Humans ,ddc:610 ,lcsh:Science ,ComputingMilieux_MISCELLANEOUS ,Aldehydes ,Cell Death ,lcsh:R ,Recombinant Proteins ,eye diseases ,Complement cascade ,Oxidative Stress ,Caspases ,Complement Factor H ,lcsh:Q ,sense organs ,Visual system - Abstract
International audience; Age Related Macular Degeneration (AMD) is the first cause of social blindness in people aged over 65 leading to atrophy of retinal pigment epithelial cells (RPE), photoreceptors and choroids, eventually associated with choroidal neovascularization. Accumulation of undigested cellular debris within RPE cells or under the RPE (Drusen), oxidative stress and inflammatory mediators contribute to the RPE cell death. The major risk to develop AMD is the Y402H polymorphism of complement factor H (CFH). CFH interacting with oxidized phospholipids on the RPE membrane modulates the functions of these cells, but the exact role of CFH in RPE cell death and survival remain poorly understood. The aim of this study was to analyze the potential protective mechanism of CFH on RPE cells submitted to oxidative stress. Upon exposure to oxidized lipids 4-HNE (4-hydroxy-2-nonenal) derived from photoreceptors, both the human RPE cell line ARPE-19 and RPE cells derived from human induced pluripotent stem cells were protected from death only in the presence of the full length human recombinant CFH in the culture medium. This protective effect was independent from the membrane attack complex (MAC) formation. CFH maintained RPE cells tight junctions’ structure and regulated the caspase dependent apoptosis process. These results demonstrated the CFH anti-oxidative stress functions independently of its capacity to inhibit MAC formation. more...
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- 2019
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Catalog
3. Lipocalin 2 as a potential systemic biomarker for central serous chorioretinopathy
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Matet, A. (A.), Jaworski, T. (T.), Bousquet, E. (E.), Canonica, J. (J.), Gobeaux, C. (C.), Daruich, A. (A.), Zhao, M. (M.), Zola, M. (M.), Meester-Smoor, M.A. (Magda), Mohabati, D. (D.), Jaisser, F. (Frederic), Yzer, S. (Suzanne), Behar-Cohen, F. (Francine), Matet, A. (A.), Jaworski, T. (T.), Bousquet, E. (E.), Canonica, J. (J.), Gobeaux, C. (C.), Daruich, A. (A.), Zhao, M. (M.), Zola, M. (M.), Meester-Smoor, M.A. (Magda), Mohabati, D. (D.), Jaisser, F. (Frederic), Yzer, S. (Suzanne), and Behar-Cohen, F. (Francine) more...
- Abstract
No systemic biomarker of Central Serous Chorioretinopathy (CSCR) has been identified. Lipocalin 2 (LCN2 or NGAL), alone or complexed with MMP-9 (NGAL/MMP-9), is increased in several retinal disorders. Serum levels of LCN2 and NGAL/MMP-9 were measured in CSCR patients (n = 147) with chronic (n = 76) or acute/recurrent disease (n = 71) and in age- and sex-matched h more...
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- 2020
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4. Lipocalin 2 as a potential systemic biomarker for central serous chorioretinopathy
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Matet, A, Jaworski, T, Bousquet, E, Canonica, J, Gobeaux, C, Daruich, A, Zhao, M, Zola, M, Meester - Smoor, Magda, Mohabati, D, Jaisser, F, Yzer, S, Behar-Cohen, F, Matet, A, Jaworski, T, Bousquet, E, Canonica, J, Gobeaux, C, Daruich, A, Zhao, M, Zola, M, Meester - Smoor, Magda, Mohabati, D, Jaisser, F, Yzer, S, and Behar-Cohen, F more...
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- 2020
5. Comparison of a Barcode-Based Smartphone Application to a Questionnaire to Assess the Use of Cleaning Products at Home and Their Association with Asthma Symptoms
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Lemire, Pierre, Temam, Sofia, Quinot, Catherine, Sévin, Etienne, Remacle, Sophie, Supernant, Karine, Dumas, Orianne, Le Moual, Nicole, Eyriey, E., Licinia, A., Vellement, A., Pin, Isabelle, Hofmann, P., Hullo, Églantine, Llerena, Catherine, Morin, X., Morlot, A., Lepeule, Johanna, Lyon-Caen, Sarah, Philippat, Claire, Quentin, Joane, Siroux, Valérie, Slama, Rémy, Faraldo, Beatrice, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, MGEN Foundation for Public Health [Paris] (FESP-MGEN), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), EpiConcept [Paris], The Sepages Study Group., Fondation d’entreprise MGEN pour la santé publique (FESP MGEN), Anses-PNR-EST-2015-1-022/Ademe-1594C0091, Anses-PNR-EST-2017-1-101/Ademe-1762C0021 Seventh Framework Programme, FP7: FP7/2007-206, N308333-HELIX European Research Council, ERC: N 311765-E-DOHaD Agence Nationale de la Recherche, ANR: 14-CE21-0007-01, 19-CE36-0003-01, ANR 18-CE36-005, ANR-12-PDOC-0029-01, ANR-15-IDEX, ANR-15-IDEX-02 Institut National de la Santé et de la Recherche Médicale, Inserm Fondation de France: CLI-MATHES—00081169 Commissariat Général à l'Investissement, CGI Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, ANSES: PNR-EST-2018-1-264 Agir pour les Maladies Chroniques, Acknowledgments: We acknowledge the role of SEPAGES cohort study group: E. Eyriey, A. Licinia, A. Vellement (Groupe Hospitalier Mutualiste, Grenoble), I. Pin, P. Hofmann, E. Hullo, C. Llerena (Grenoble University Hospital, La Tronche), X. Morin (Clinique des Cèdres, Echirolles), A. Morlot (Clinique Belledonne, Saint-Martin d’Hères), J. Lepeule, S. Lyon-Caen, C. Philippat, I. Pin, J. Quentin, V. Siroux, R. Slama (Inserm, CNRS, University Grenoble Alpes IAB research center). We thank A. Benlakhryfa, L. Borges, Y. Gioria, clinical research assistants, J. Giraud, M. Marceau, M.-P. Martin, nurses, E. Charvet, A. Putod, midwives, M. Graca, K. Gridel, C. Pelini, fieldworkers, K. Guichardet, A. Levanic, C. Martel, E. Quinteiro neuropsychologists, the sta↵ from Grenoble Center for Clinical Investigation (CIC): J.-L. Cracowski, C. Cracowski, E. Hodaj, D. Abry, N. Gonnet and A. Tournier. A warm thank you also to M. Althuser, S. Althuser, F. Camus-Chauvet, P. Dusonchet, S. Dusonchet, L. Emery, P. Fabbrizio, P. Ho↵mann, D. Marchal André, X. Morin, E. Opoix, L. Pacteau, P. Rivoire, A. Royannais, C. Tomasella, T. Tomasella, D. Tournadre, P. Viossat, E. Volpi, S. Rey, E. Warembourg and clinicians from Grenoble University Hospital for their support in the recruitment of the study volunteers. We also thank A. Buchet, S.F. Caraby, J.-N. Canonica, J. Dujourdil, E. Eyriey, P. Hofmann, M. Jeannin, A. Licina, X. Morin, A. Nicolas, and all midwives from the four maternity wards of Grenoble urban areas. We thank B. Chevolon, C. Cornes, A.S. Gauchez, D. Guergour, P. Faure, J. Arnaud for thyroid hormones assessment. We thank the team of L. Chaperod (EFS) for its implication on the immunological aspects of the project. We thank G. Uzu (IRD) and J.-L. Ja↵rezo (CNRS) for their implication on PM oxidative potential assessment. We thank F.-X. Leupert, O. Bonnet and L. Goirand for the access to the birth certificate database from the Conseil Général de l’Isère. Sépages biospecimens are stored at Grenoble University Hospital (CHU-GA) biobank (bb-0033-00069), we would like to thank the whole CRB team, led by P. Mossuz and P. Lorimier, and in particular the technicians for the huge work of biospecimens processing and pooling: W. Jayar and L. Than, as well as G. Schummer. The Internet platform for secured data collection was developed by Epiconcept Paris (E. Sevin, S. Ployart, A. Polaert). SEPAGES data are stored thanks to Inserm RE-CO-NAI platform funded by Commissariat Général à l’Investissement, with the implication of Sophie de Visme (Inserm DSI). Many thanks to M.A. Charles, RE-CO-NAI coordinator, for her support. Finally, and importantly, we would like to express our sincere thanks to participants of the SEPAGES study. The authors are grateful for the help received from Ines Taarit and Mathias Clément to update the cleaning products ingredients database., Funding: The cohort was supported by the European Research Council (consolidator grant N 311765-E-DOHaD, PI, R. Slama), by the European Community’s Seventh Framework Programme (FP7/2007-206, grant N308333-HELIX, PI, M. Vrijheid), by ANR, the French Research Agency (PAPER project ANR-12-PDOC-0029-01, PI, J. Lepeule, SHALCOH project, 14-CE21-0007-01, PI, R. Slama, GUMME project, PI, R. Slama, ETAPE ANR 18-CE36-005, PI, J. Lepeule, EDeN project 19-CE36-0003-01, SYMER project, ANR-15-IDEX-02, PI, U. Schlattner, Mobil’Air project, ANR-15-IDEX, PI, S. Mathy, supported by University Grenoble-3Alpes), by ANSES (CNAP and HYPAXE projects, PI C. Philippat, PENDORE project, PNR-EST-2018-1-264, PI, V. Siroux), by Plan Cancer (Canc’Air project, PI, P. Guénel), by Association de Recherche sur le Cancer (ARC, PI, P. Guénel), by AGIR pour les maladies chroniques (PI, R. Slama and PRENAPAR project, V. Siroux), and Fonds de Recherche pour la Santé Respiratoire (FRSR, PI, I. Pin) and by Fondation de France (CLI-MATHES—00081169, J. Lepeule). We acknowledge the support of ANSES, Inserm and AGIR pour les maladies chroniques, for SEPAGES feasibility study. The support of 'SCUSI 2017' Région Auvergne-Rhône-Alpes programme is also acknowledged. COBANET-Sepages project was support by Anses and Ademe (COBANET: Anses-PNR-EST-2015-1-022/Ademe-1594C0091, PI: N Le Moual, CRESPINET: Anses-PNR-EST-2017-1-101/Ademe-1762C0021, PI: N Le Moual). Pierre Lemire benefited from a PhD scholarship of the University of Paris-Sud/Paris-Saclay, France., The cohort was supported by the European Research Council (consolidator grant N 311765-E-DOHaD, PI, R. Slama), by the European Community?s Seventh Framework Programme (FP7/2007-206, grant N308333-HELIX, PI, M. Vrijheid), by ANR, the French Research Agency (PAPER project ANR-12-PDOC-0029-01, PI, J. Lepeule, and EDeN project 19-CE36-0003-01, SYMER project, ANR-15-IDEX-02, PI, U. Schlattner, Mobil?Air project, ANR-15-IDEX, PI, S. Mathy, supported by University Grenoble-3Alpes), by ANSES (CNAP and HYPAXE projects, PI C. Philippat, PENDORE project, PNR-EST-2018-1-264, PI, V. Siroux), by Plan Cancer (Canc?Air project, PI, P. Gu?nel), by Association de Recherche sur le Cancer (ARC, PI, P. Gu?nel), by AGIR pour les maladies chroniques (PI, R. Slama and PRENAPAR project, V. Siroux), and Fonds de Recherche pour la Sant? Respiratoire (FRSR, PI, I. Pin) and by Fondation de France (CLIMATHES?00081169, J. Lepeule). We acknowledge the support of ANSES, Inserm and AGIR pour les maladies chroniques, for SEPAGES feasibility study. The support of ?SCUSI 2017? R?gion Auvergne-Rh?ne-Alpes programme is also acknowledged. COBANET-Sepages project was support by Anses and Ademe (COBANET: Anses-PNR-EST-2015-1-022/Ademe-1594C0091, PI: N Le Moual more...
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medicine.medical_specialty ,Health, Toxicology and Mutagenesis ,[SDV]Life Sciences [q-bio] ,lcsh:Medicine ,Smartphone application ,Logistic regression ,Article ,03 medical and health sciences ,0302 clinical medicine ,Surveys and Questionnaires ,Environmental health ,Epidemiology ,Odds Ratio ,medicine ,Humans ,030212 general & internal medicine ,Association (psychology) ,smartphone application ,Asthma ,household cleaning products ,business.industry ,lcsh:R ,Public Health, Environmental and Occupational Health ,Asthma symptoms ,Odds ratio ,asthma ,medicine.disease ,3. Good health ,030228 respiratory system ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Female ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Smartphone ,business ,Kappa ,Disinfectants - Abstract
International audience; Household disinfectant and cleaning products (HDCPs) assessment is challenging in epidemiological research. We hypothesized that a newly-developed smartphone application was more objective than questionnaires in assessing HDCPs. Therefore, we aimed to compare both methods, in terms of exposure assessments and respiratory health effects estimates. The women of the SEPAGES birth cohort completed repeated validated questionnaires on HDCPs and respiratory health and used an application to report HDCPs and scan products barcodes, subsequently linked with an ingredients database. Agreements between the two methods were assessed by Kappa coefficients. Logistic regression models estimated associations of HDCP with asthma symptom score. The 101 participants (18 with asthma symptom score ≥1) scanned 617 different products (580 with available ingredients list). Slight to fair agreements for sprays, bleach and scented HDCP were observed (Kappa: 0.35, 0.25, 0.11, respectively). Strength of the associations between HDCP and asthma symptom score varied between both methods but all odds ratios (OR) were greater than one. The number of scanned products used weekly was significantly associated with the asthma symptom score (adjusted-OR [CI 95%]: 1.15 [1.00–1.32]). This study shows the importance of using novel tools in epidemiological research to objectively assess HDCP and therefore reduce exposure measurement errors. more...
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- 2021
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6. Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion.
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Canonica J, Foxton R, Garrido MG, Lin CM, Uhles S, Shanmugam S, Antonetti DA, Abcouwer SF, and Westenskow PD
- Abstract
Introduction: Clinical trials demonstrated that co-targeting angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF-A) with faricimab controls anatomic outcomes and maintains vision improvements, with strong durability, through 2 years in patients with neovascular age-related macular degeneration and diabetic macular edema. The mechanism(s) underlying these findings is incompletely understood and the specific role that Ang-2 inhibition plays requires further investigation., Methods: We examined the effects of single and dual Ang-2/VEGF-A inhibition in diseased vasculatures of JR5558 mice with spontaneous choroidal neovascularization (CNV) and in mice with retinal ischemia/reperfusion (I/R) injuries., Results: In JR5558 mice, Ang-2, VEGF-A, and dual Ang-2/VEGF-A inhibition reduced CNV area after 1 week; only dual Ang-2/VEGF-A inhibition decreased neovascular leakage. Only Ang-2 and dual Ang-2/VEGF-A inhibition maintained reductions after 5 weeks. Dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 1 week. Both Ang-2 and dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 5 weeks. In the retinal I/R injury model, dual Ang-2/VEGF-A inhibition was statistically significantly more effective than Ang-2 or VEGF-A inhibition alone in preventing retinal vascular leakage and neurodegeneration., Discussion: These data highlight the role of Ang-2 in dual Ang-2/VEGF-A inhibition and indicate that dual inhibition has complementary anti-inflammatory and neuroprotective effects, suggesting a mechanism for the durability and efficacy of faricimab in clinical trials., Competing Interests: JC, RF, SU, and PW are employees of F. Hoffmann-La Roche Ltd., Roche Pharma AG, or Genentech, Inc. MG was an employee of F. Hoffmann-La Roche Ltd. at the time the studies described in this manuscript were performed and is a current employee of Boehringer Ingelheim (Schweiz) GmbH. DA and SA have received research funding from F. Hoffmann-La Roche Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from F. Hoffmann-La Roche Ltd. The funder had the following involvement with the study: study design; conducting the study; data collection, management, analysis, interpretation, preparation, review, and approval of the manuscript. Funding was provided by F. Hoffmann-La Roche Ltd. for third-party writing assistance, which was provided by Luke Carey, Ph.D., CMPP, of Envision Pharma Group., (Copyright © 2023 Canonica, Foxton, Garrido, Lin, Uhles, Shanmugam, Antonetti, Abcouwer and Westenskow.) more...
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- 2023
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7. Preventing VEGF-Mediated Vascular Permeability by Experimentally Potentiating BBB Characteristics in Endothelial Cells.
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Kim BK, Canonica J, Roudnicky F, and Westenskow PD
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- Animals, Blood-Brain Barrier metabolism, Blood-Retinal Barrier metabolism, Human Umbilical Vein Endothelial Cells metabolism, Humans, Reproducibility of Results, Capillary Permeability physiology, Vascular Endothelial Growth Factor A metabolism
- Abstract
Difficulties with poor reproducibility and translatability of animal model-based research, along with increased efforts to abide by the 3Rs tenet of animal welfare, are driving demand for more relevant human cellular systems. This is especially true for central nervous system (CNS) vasculatures with specialized properties and barriers, namely the blood-brain and blood-retinal barriers (BBB and BRB, respectively) which are difficult to model in vitro. The BBB and BRB protect neurovascular units by regulating nutrient homeostasis, maintaining local ion levels, protecting against exposure from circulating toxins and pathogens, and restricting passage of peripheral immune factors. In this manuscript, we will describe transgenic and pharmacological-based protocols to generate relevant BBB and BRB models both from human pluripotent stem cell-derived endothelial cells (hPSC-ECs) and from primary human umbilical vein endothelial cells (HUVECs). When followed, researchers can expect to generate well-characterized, anatomical and functional BBB and BRB EC monolayers in 36-48 h that are stable up to 90 h. The ability to generate more relevant BBB and BRB EC cultures will improve drug discovery efforts and inform future therapies for neurovascular disorders., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.) more...
- Published
- 2022
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8. Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium.
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Canonica J, Zhao M, Favez T, Gelizé E, Jonet L, Kowalczuk L, Guegan J, Le Menuet D, Viengchareun S, Lombès M, Pussard E, Arsenijevic Y, and Behar-Cohen F
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- Animals, Epithelial-Mesenchymal Transition, Extracellular Matrix genetics, Extracellular Matrix metabolism, Extracellular Matrix pathology, Humans, Mice, Mice, Transgenic, Pluripotent Stem Cells pathology, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Receptors, Mineralocorticoid genetics, Retinal Diseases genetics, Retinal Diseases pathology, Retinal Pigment Epithelium pathology, Aldosterone metabolism, Hydrocortisone metabolism, Pluripotent Stem Cells metabolism, Receptors, Mineralocorticoid metabolism, Retinal Diseases metabolism, Retinal Pigment Epithelium metabolism
- Abstract
Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood-retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone-an MR-specific agonist, or cortisol or cortisol + RU486-a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling ( CNN1 , MGP , AMTN) , epithelial-mesenchymal transition, RPE cell proliferation and migration ( ITGB3 , PLAUR and FOSL1 ) and immune balance ( TNFSF18 and PTX3 ). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology. more...
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- 2021
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9. Critical role of the mineralocorticoid receptor in aldosterone-dependent and aldosterone-independent regulation of ENaC in the distal nephron.
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Nesterov V, Bertog M, Canonica J, Hummler E, Coleman R, Welling PA, and Korbmacher C
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- Aldosterone metabolism, Animals, Epithelial Sodium Channels metabolism, Mice, Nephrons metabolism, Sodium metabolism, Sodium, Dietary metabolism, Aldosterone pharmacokinetics, Kidney Tubules, Collecting metabolism, Potassium metabolism, Receptors, Mineralocorticoid drug effects, Receptors, Mineralocorticoid metabolism
- Abstract
The epithelial Na
+ channel (ENaC) constitutes the rate-limiting step for Na+ absorption in the aldosterone-sensitive distal nephron (ASDN) comprising the late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). Previously, we demonstrated that ENaC activity in the DCT2/CNT transition zone is constitutively high and independent of aldosterone, in contrast to its aldosterone dependence in the late CNT/initial cortical CD (CCD). The mineralocorticoid receptor (MR) is expressed in the entire ASDN. Its activation by glucocorticoids is prevented through 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) abundantly expressed in the late but probably not early part of the ASDN. We hypothesized that ENaC function in the early part of the ASDN is aldosterone independent but may depend on MR activated by glucocorticoids due to low 11β-HSD2 abundance. To test this hypothesis, we used doxycycline-inducible nephron-specific MR-deficient [MR knockout (KO)] mice. Whole cell ENaC currents were investigated in isolated nephron fragments from the DCT2/CNT or CNT/CCD transition zones using the patch-clamp technique. ENaC activity was detectable in the CNT/CCD of control mice but absent or barely detectable in the majority of CNT/CCD preparations from MR KO mice. Importantly, ENaC currents in the DCT2/CNT were greatly reduced in MR KO mice compared with ENaC currents in the DCT2/CNT of control mice. Immunofluorescence for 11β-HSD2 was abundant in the CCD, less prominent in the CNT, and very low in the DCT2. We conclude that MR is critically important for maintaining aldosterone-independent ENaC activity in the DCT2/CNT. Aldosterone-independent MR activation is probably mediated by glucocorticoids due to low expression of 11β-HSD2. NEW & NOTEWORTHY Using a mouse model with inducible nephron-specific mineralocorticoid receptor (MR) deficiency, we demonstrated that MR is not only critical for maintaining aldosterone-dependent ENaC activity in CNT/CCD but also for aldosterone-independent ENaC activity in DCT2/CNT. Furthermore, we demonstrated that cells of this latter nephron segment express little 11β-HSD2, which probably allows glucocorticoids to stimulate MR, resulting in aldosterone-independent ENaC activity in DCT2/CNT. This site-specific ENaC regulation has physiologically relevant implications for renal sodium and potassium homeostasis. more...- Published
- 2021
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10. Meteorin Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration.
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Delaunay K, Sellam A, Dinet V, Moulin A, Zhao M, Gelizé E, Canonica J, Naud MC, Crisanti-Lassiaz P, and Behar-Cohen F
- Abstract
The aim of this study was to evaluate the potential anti-angiogenic effect of MTRN (meteorin) in the laser-induced CNV rat model and explore its mechanisms of action. MTRN, thrompospondin-1, glial cell markers (GFAP, vimentin), and phalloidin were immuno-stained in non-human primate flat-mounted retinas and human retina cross sections. The effect of MTRN at different doses and time points was evaluated on laser-induced CNV at 14 days using in vivo fluorescein angiography and ex vivo quantification of CNV. A pan transcriptomic analysis of the retina and the RPE/choroid complex was used to explore MTRN effects mechanisms. In human retina, MTRN is enriched in the macula, expressed in and secreted by glial cells, and located in photoreceptor cells, including in nuclear bodies. Intravitreal MTRN administered preventively reduced CNV angiographic scores and CNV size in a dose-dependent manner. The highest dose, administered at day 7, also reduced CNV. MTRN, which is regulated by mineralocorticoid receptor modulators in the rat retina, regulates pathways associated with angiogenesis, oxidative stress, and neuroprotection. MTRN is a potential novel therapeutic candidate protein for wet AMD. more...
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- 2021
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11. Deletion of the serine protease CAP2/Tmprss4 leads to dysregulated renal water handling upon dietary potassium depletion.
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Keppner A, Maric D, Sergi C, Ansermet C, De Bellis D, Kratschmar DV, Canonica J, Klusonova P, Fenton RA, Odermatt A, Crambert G, Hoogewijs D, and Hummler E
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- 11-beta-Hydroxysteroid Dehydrogenase Type 2 genetics, Adaptor Proteins, Signal Transducing genetics, Animals, Blotting, Western, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Kidney metabolism, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Potassium, Dietary metabolism, Receptors, Glucocorticoid metabolism, Reverse Transcriptase Polymerase Chain Reaction, Serine Endopeptidases genetics, Serine Endopeptidases metabolism, Solute Carrier Family 12, Member 1 metabolism, 11-beta-Hydroxysteroid Dehydrogenase Type 2 metabolism, Adaptor Proteins, Signal Transducing metabolism, Aquaporin 2 metabolism
- Abstract
The kidney needs to adapt daily to variable dietary K
+ contents via various mechanisms including diuretic, acid-base and hormonal changes that are still not fully understood. In this study, we demonstrate that following a K+ -deficient diet in wildtype mice, the serine protease CAP2/Tmprss4 is upregulated in connecting tubule and cortical collecting duct and also localizes to the medulla and transitional epithelium of the papilla and minor calyx. Male CAP2/Tmprss4 knockout mice display altered water handling and urine osmolality, enhanced vasopressin response leading to upregulated adenylate cyclase 6 expression and cAMP overproduction, and subsequently greater aquaporin 2 (AQP2) and Na+ -K+ -2Cl- cotransporter 2 (NKCC2) expression following K+ -deficient diet. Urinary acidification coincides with significantly increased H+ ,K+ -ATPase type 2 (HKA2) mRNA and protein expression, and decreased calcium and phosphate excretion. This is accompanied by increased glucocorticoid receptor (GR) protein levels and reduced 11β-hydroxysteroid dehydrogenase 2 activity in knockout mice. Strikingly, genetic nephron-specific deletion of GR leads to the mirrored phenotype of CAP2/Tmprss4 knockouts, including increased water intake and urine output, urinary alkalinisation, downregulation of HKA2, AQP2 and NKCC2. Collectively, our data unveil a novel role of the serine protease CAP2/Tmprss4 and GR on renal water handling upon dietary K+ depletion. more...- Published
- 2019
- Full Text
- View/download PDF
12. Effect of acute and chronic aldosterone exposure on the retinal pigment epithelium-choroid complex in rodents.
- Author
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Canonica J, Mehanna C, Bonnard B, Jonet L, Gelize E, Jais JP, Jaisser F, Zhao M, and Behar-Cohen F
- Subjects
- Acute Disease, Animals, Blood Pressure drug effects, Cell Movement, Choroid metabolism, Choroid pathology, Choroid Diseases chemically induced, Choroid Diseases diagnosis, Chronic Disease, Disease Models, Animal, Intravitreal Injections, Male, Mice, Mice, Inbred C57BL, Nephrectomy, Papilledema chemically induced, Papilledema diagnosis, Rats, Rats, Inbred Lew, Real-Time Polymerase Chain Reaction, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium pathology, Sequence Analysis, RNA, Tomography, Optical Coherence, Aldosterone pharmacology, Choroid drug effects, Eye Proteins genetics, Gene Expression Regulation physiology, Retinal Pigment Epithelium drug effects
- Abstract
Preclinical and clinical evidences show that aldosterone and/or mineralocorticoid receptor (MR) over-activation by glucocorticoids can be deleterious to the retina and to the retinal pigment epithelium (RPE)-choroid complex. However, the exact molecular mechanisms driving these effects remain poorly understood and pathological consequences of chronic exposure of the retina and RPE/choroid to aldosterone have not been completely explored. We aimed to decipher the transcriptomic regulation in the RPE-choroid complex in rats in response to acute intraocular aldosterone injection and to explore the consequences of systemic chronic aldosterone exposure on the morphology and the gene regulation in RPE/choroid in mice. High dose of aldosterone (100 nM) was intravitreously injected in Lewis rat eyes in order to yield an aldosterone dose able to induce a molecular response at the apical side of the RPE-choroid complex. The posterior segment morphology was evaluated in vivo using optical coherence tomography (OCT) before and 24 h after aldosterone injection. Rat RPE-choroid complexes were used for RNA sequencing and analysis. Uninephrectomy/aldosterone/salt (NAS) model was created in wild-type C57BL/6 mice. After 6 weeks, histology of mouse posterior segments were observed ex vivo. Gene expression in the RPE-choroid complex was analyzed using quantitative PCR. Acute intravitreous injection of aldosterone induced posterior segment inflammation observed on OCT. RNA sequencing of rat RPE-choroid complexes revealed up-regulation of pathways involved in inflammation, oxidative stress and RNA procession, and down-regulation of genes involved in synaptic activity, muscle contraction, cytoskeleton, cell junction and transporters. Chronic aldosterone/salt exposure in NAS model induces retinal edema, choroidal vasodilation and RPE cell dysfunction and migration. Quantitative PCR showed deregulation of genes involved in inflammatory response, oxidative stress, particularly the NOX pathway, angiogenesis and cell contractility. Both rodent models share some common phenotypes and molecular regulations in the RPE-choroid complex that could contribute to pachychoroid epitheliopathy in humans. The difference in inflammatory status relies on different intraocular or systemic route of aldosterone administration and on the different doses of aldosterone exposed to the RPE-choroid complex., (Copyright © 2019 Elsevier Ltd. All rights reserved.) more...
- Published
- 2019
- Full Text
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13. CFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex.
- Author
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Borras C, Canonica J, Jorieux S, Abache T, El Sanharawi M, Klein C, Delaunay K, Jonet L, Salvodelli M, Naud MC, Arsenijevic Y, Shalabi A, Souchaud L, Behar-Cohen F, and Dinet V
- Subjects
- Aldehydes pharmacology, Apoptosis drug effects, Blotting, Western, Caspases metabolism, Cell Death drug effects, Cell Line, Complement Membrane Attack Complex metabolism, Humans, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells metabolism, Microscopy, Electron, Transmission, Oxidative Stress drug effects, Real-Time Polymerase Chain Reaction, Recombinant Proteins, Retinal Pigment Epithelium metabolism, Tight Junctions drug effects, Complement Factor H pharmacology, Complement Membrane Attack Complex drug effects, Retinal Pigment Epithelium drug effects
- Abstract
Age Related Macular Degeneration (AMD) is the first cause of social blindness in people aged over 65 leading to atrophy of retinal pigment epithelial cells (RPE), photoreceptors and choroids, eventually associated with choroidal neovascularization. Accumulation of undigested cellular debris within RPE cells or under the RPE (Drusen), oxidative stress and inflammatory mediators contribute to the RPE cell death. The major risk to develop AMD is the Y402H polymorphism of complement factor H (CFH). CFH interacting with oxidized phospholipids on the RPE membrane modulates the functions of these cells, but the exact role of CFH in RPE cell death and survival remain poorly understood. The aim of this study was to analyze the potential protective mechanism of CFH on RPE cells submitted to oxidative stress. Upon exposure to oxidized lipids 4-HNE (4-hydroxy-2-nonenal) derived from photoreceptors, both the human RPE cell line ARPE-19 and RPE cells derived from human induced pluripotent stem cells were protected from death only in the presence of the full length human recombinant CFH in the culture medium. This protective effect was independent from the membrane attack complex (MAC) formation. CFH maintained RPE cells tight junctions' structure and regulated the caspase dependent apoptosis process. These results demonstrated the CFH anti-oxidative stress functions independently of its capacity to inhibit MAC formation. more...
- Published
- 2019
- Full Text
- View/download PDF
14. Lack of Renal Tubular Glucocorticoid Receptor Decreases the Thiazide-Sensitive Na + /Cl - Cotransporter NCC and Transiently Affects Sodium Handling.
- Author
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Canonica J, Frateschi S, Boscardin E, Ebering A, Sergi C, Jäger Y, Peyrollaz T, Mérillat AM, Maillard M, Klusonova P, Odermatt A, Koesters R, Debonneville A, Staub O, Verouti SN, and Hummler E
- Abstract
Chronic glucocorticoid infusion impairs NCC activity and induces a non-dipping profile in mice, suggesting that glucocorticoids are essential for daily blood pressure variations. In this paper, we studied mice lacking the renal tubular glucocorticoid receptor (GR) in adulthood (GR knockouts, Nr3c1
Pax8/LC1 ). Upon standard salt diet, Nr3c1Pax8/LC1 mice grow normally, but show reduced NCC activity despite normal plasma aldosterone levels. Following diet switch to low sodium, Nr3c1Pax8/LC1 mice exhibit a transient but significant reduction in the activity of NCC and expression of NHE3 and NKCC2 accompanied by significant increased Spak activity. This is followed by transiently increased urinary sodium excretion and higher plasma aldosterone concentrations. Plasma corticosterone levels and 11βHSD2 mRNA expression and activity in the whole kidney remain unchanged. High salt diet does not affect whole body Na+ and/or K+ balance and NCC activity is not reduced, but leads to a significant increase in diastolic blood pressure dipping in Nr3c1Pax8/LC1 mice. When high sodium treatment is followed by 48 h of darkness, NCC abundance is reduced in knockout mice although activity is not different. Our data show that upon Na+ restriction renal tubular GR-deficiency transiently affects Na+ handling and transport pathways. Overall, upon standard, low Na+ and high Na+ diet exposure Na+ and K+ balance is maintained as evidenced by normal plasma and urinary Na+ and K+ and aldosterone concentrations. more...- Published
- 2019
- Full Text
- View/download PDF
15. Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration.
- Author
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Zhao M, Mantel I, Gelize E, Li X, Xie X, Arboleda A, Seminel M, Levy-Boukris R, Dernigoghossian M, Prunotto A, Andrieu-Soler C, Rivolta C, Canonica J, Naud MC, Lechner S, Farman N, Bravo-Osuna I, Herrero-Vanrell R, Jaisser F, and Behar-Cohen F more...
- Subjects
- Aged, Aged, 80 and over, Animals, Choroid drug effects, Choroid metabolism, Choroid pathology, Choroidal Neovascularization genetics, Choroidal Neovascularization metabolism, Choroidal Neovascularization pathology, Drug Compounding methods, Female, Gene Expression, Humans, Intravitreal Injections, Macular Degeneration genetics, Macular Degeneration metabolism, Macular Degeneration pathology, Male, Mice, Mice, Transgenic, Microspheres, Pilot Projects, Prospective Studies, Ranibizumab therapeutic use, Rats, Long-Evans, Receptors, Mineralocorticoid metabolism, Receptors, Vascular Endothelial Growth Factor therapeutic use, Recombinant Fusion Proteins therapeutic use, Treatment Outcome, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Angiogenesis Inhibitors therapeutic use, Choroidal Neovascularization drug therapy, Macular Degeneration drug therapy, Mineralocorticoid Receptor Antagonists therapeutic use, Receptors, Mineralocorticoid genetics, Spironolactone therapeutic use
- Abstract
Choroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), particularly when refractory to intraocular anti-VEGF injections. Here we report that treatment with the oral mineralocorticoid receptor (MR) antagonist spironolactone reduces signs of CNV in patients refractory to anti-VEGF treatment. In animal models of wet AMD, pharmacological inhibition of the MR pathway or endothelial-specific deletion of MR inhibits CNV through VEGF-independent mechanisms, in part through upregulation of the extracellular matrix protein decorin. Intravitreal injections of spironolactone-loaded microspheres and systemic delivery lead to similar reductions in CNV. Together, our work suggests MR inhibition as a novel therapeutic option for wet AMD patients unresponsive to anti-VEGF drugs. more...
- Published
- 2019
- Full Text
- View/download PDF
16. Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype.
- Author
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Canonica J, Sergi C, Maillard M, Klusonova P, Odermatt A, Koesters R, Loffing-Cueni D, Loffing J, Rossier B, Frateschi S, and Hummler E
- Subjects
- Aldosterone blood, Animals, Epithelial Cells metabolism, Epithelial Sodium Channels genetics, Epithelial Sodium Channels metabolism, Gene Deletion, Mice, Potassium blood, Potassium urine, Pseudohypoaldosteronism genetics, Pseudohypoaldosteronism pathology, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Receptors, Mineralocorticoid genetics, Receptors, Mineralocorticoid metabolism, Sodium blood, Sodium urine, Sodium Chloride Symporters genetics, Sodium Chloride Symporters metabolism, Weight Loss, Nephrons metabolism, Phenotype, Pseudohypoaldosteronism metabolism, Receptors, Mineralocorticoid deficiency
- Abstract
Aldosterone is the main mineralocorticoid hormone controlling sodium balance, fluid homeostasis, and blood pressure by regulating sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN). Germline loss-of-function mutations of the mineralocorticoid receptor (MR) in humans and in mice lead to the "renal" form of type 1 pseudohypoaldosteronism (PHA-1), a case of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia, and metabolic acidosis. To investigate the importance of MR in adult epithelial cells, we generated nephron-specific MR knockout mice (MR(Pax8/LC1)) using a doxycycline-inducible system. Under standard diet, MR(Pax8/LC1) mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MR(Pax8/LC1) mice survive but develop a severe PHA-1 phenotype with higher urinary Na(+) levels, decreased plasma Na(+), hyperkalemia, and higher levels of plasma aldosterone. This phenotype further worsens and becomes lethal under a sodium-deficient diet. Na(+)/Cl(-) co-transporter (NCC) protein expression and its phosphorylated form are downregulated in the MR(Pax8/LC1) knockouts, as well as the αENaC protein expression level, whereas the expression of glucocorticoid receptor (GR) is increased. A diet rich in Na(+) and low in K(+) does not restore plasma aldosterone to control levels but is sufficient to restore body weight, plasma, and urinary electrolytes. In conclusion, MR deletion along the nephron fully recapitulates the features of severe human PHA-1. ENaC protein expression is dependent on MR activity. Suppression of NCC under hyperkalemia predominates in a hypovolemic state. more...
- Published
- 2016
- Full Text
- View/download PDF
17. [Therapeutic drug mishaps in a medical emergency service].
- Author
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Carpentier F, Mingat J, Canonica JN, Saviuc P, Barnoud D, Martin-Barbaz F, and Guignier M
- Subjects
- Age Factors, Female, France, Humans, Male, Middle Aged, Pharmaceutical Preparations administration & dosage, Poisoning epidemiology, Prospective Studies, Sex Factors, Drug-Related Side Effects and Adverse Reactions, Emergency Service, Hospital statistics & numerical data
- Published
- 1986
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