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12 results on '"MESH: Glomerulonephritis, Membranous"'

1. Circulating Antipodocyte Antibodies in Membranous Nephropathy: Pathophysiologic and Clinical Relevance

Author

Kimura, Yukihiro, Morita, Hiroyuki, Debiec, Hanna, Yamada, Harutaka, Miura, Naoto, Banno, Shogo, Ronco, Pierre, Imai, Hirokazu, Division of Nephrology and Rheumatology, Aichi Medical University School of Medicine, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Internal Medicine, Kawana Hospital, This work was partially supported by a grant from the Aichi Medical University Alumni Association, RONCO, Pierre, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Pathology, medicine.medical_specialty, alpha-enolase, MESH: Glomerulonephritis, Membranous, 030232 urology & nephrology, Glomerulonephritis, Membranous, 03 medical and health sciences, 0302 clinical medicine, Membranous nephropathy, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Podocytes, medicine, Animals, Humans, MESH: Autoantibodies, MESH: Animals, Clinical significance, ComputingMilieux_MISCELLANEOUS, Autoantibodies, 030304 developmental biology, 0303 health sciences, phospholipase A2 receptor, MESH: Humans, biology, Podocytes, business.industry, membranous nephropathy, medicine.disease, Pathophysiology, 3. Good health, Nephrology, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Antibody, business
Abstract

International audience

Published
2013
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2. Phospholipase A2 Receptor (PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy

Author

S. H. Powis, Robert Kleta, Marieke J H Coenen, Anne Boland-Augé, Peter W. Mathieson, Paul Brenchley, Hanna Debiec, Jack F.M. Wetzels, Johanne M. Groothuismink, Bénédicte Stengel, Horia Stanescu, Alan Medlar, Julia M. Hofstra, Pierre Ronco, Detlef Bockenhauer, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Nephrology [Nijmegen, The Netherlands], Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Nephrology [London, UK], University College of London [London] (UCL), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Academic Renal Unit [Bristol, UK], University of Bristol [Bristol], School of Biomedicine [Manchester, UK], University of Manchester [Manchester], The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement 2012-305608 'European Consortium for High-Throughput Research in Rare Kidney Diseases' (EURenOmics)' (to P.W.M., P.E.B., R.K., J.F.M.W., P.R.), by the David and Elaine Potter Charitable Foundation (to S.H.P., R.K.), by the Dutch Kidney Foundation (J.M.H., grant KJPB11.021), and by the FrenchFoundation for Medical Research (H.D., P.R., grant 2012). The French Gn-Progress cohort was supported by grants from the French Ministry of Health (PHRC AOM 00022), the Ministry of Research (Decision d’aide 01P0513), and the Biomedicine Agency (AO Recherche et Greffes 2005)., Department of Human Genetics, Department of nephrology, Remodelage et Reparation du Tissu Renal, Centre for Nephrology, Equipe 10, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Academic Renal Unit, School of Biomedicine, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement 2012-305608 'European Consortium for High-Throughput Research in Rare Kidney Diseases' (EURenOmics)'(to P.W.M., P.E.B., R.K., J.F.M.W., P.R.), by the David and Elaine Potter Charitable Foundation (to S.H.P., R.K.), by the Dutch Kidney Foundation (J.M.H., grant KJPB11.021), and by the French Foundation for Medical Research (H.D., P.R., grant 2012). The French Gn-Progress cohort was supported by grants from the French Ministry of Health (PHRC AOM 00022), the Ministry of Research (Decision d'aide 01P0513), and the Biomedicine Agency (AO Recherche et Greffes 2005)., RONCO, Pierre, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Département de Néphrologie = Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Radboud University Medical Centre [Nijmegen, The Netherlands], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
Male, MESH: Sequence Analysis, DNA, MESH: Glomerulonephritis, Membranous, 030232 urology & nephrology, Glomerulonephritis, Membranous, Exon, 0302 clinical medicine, Coding region, MESH: Genomic Structural Variation, Renal disorder [IGMD 9], MESH: Aged, Genetics, Sanger sequencing, 0303 health sciences, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, General Medicine, Middle Aged, 3. Good health, Nephrology, symbols, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Adult, dbSNP, Sequence analysis, Biology, Polymorphism, Single Nucleotide, Mental health [NCEBP 9], Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, symbols.namesake, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Receptors, Phospholipase A2, Humans, Genetic Predisposition to Disease, Allele, 1000 Genomes Project, Genomic disorders and inherited multi-system disorders Molecular epidemiology [IGMD 3], Gene, Aged, 030304 developmental biology, MESH: Humans, Receptors, Phospholipase A2, MESH: Adult, Sequence Analysis, DNA, Molecular biology, MESH: Male, Genomic Structural Variation, MESH: Female
Abstract

International audience; The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (

Published
2013
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3. Pathogenesis of membranous nephropathy: recent advances and future challenges

Author

Pierre Ronco, Hanna Debiec, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), The research of the authors is supported by grants from Agence Nationale de la Recherche (ANR‑07-Physio‑016-01), and Coordination Theme 1 (Health) of the European Community's Seventh Framework Programme, grant agreement number HEALTH‑F2‑2007‑201,590., and RONCO, Pierre

Subjects
Pathology, medicine.medical_specialty, MESH: Glomerulonephritis, Membranous, 030232 urology & nephrology, Disease, Glomerulonephritis, Membranous, HLA-DQ alpha-Chains, Antigen-Antibody Reactions, Pathogenesis, 03 medical and health sciences, Heymann Nephritis, 0302 clinical medicine, Membranous nephropathy, Antigen, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: HLA-DQ alpha-Chains, MESH: Receptors, Phospholipase A2, MESH: Antigen-Antibody Reactions, MESH: Autoantibodies, Animals, Humans, Medicine, MESH: Animals, Neprilysin, Autoantibodies, 030304 developmental biology, 0303 health sciences, MESH: Humans, biology, MESH: Neprilysin, business.industry, Receptors, Phospholipase A2, Glomerulonephritis, medicine.disease, 3. Good health, Nephrology, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Antibody, business
Abstract

International audience; Over the past few years, considerable advances have been made in our understanding of the molecular pathomechanisms of human membranous nephropathy, inspired by studies of Heymann nephritis, a faithful experimental model of this disease. This research led to the identification of neutral endopeptidase, the M-type receptor for secretory phospholipase A(2) (PLA(2)R1) and cationic bovine serum albumin as target antigens of circulating and deposited antibodies in alloimmune neonatal, adult 'idiopathic' and early-childhood membranous nephropathy, respectively. A genome-wide association study has provided further evidence for a highly significant association between PLA2R1 and HLA-DQA1 loci and idiopathic membranous nephropathy in patients of white ancestry. Additional antibody specificities for cytoplasmic antigens have also been identified, but their pathogenic role is uncertain. The time has come to revisit the spectrum of membranous nephropathies based on the newly identified antigen-antibody systems that should be considered as molecular signatures of the disease and that challenge the uniform histological definition. These signatures will soon have a major impact on patient care.

Published
2012
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4. C3 nephritic factor can be associated with membranous glomerulonephritis

Author

Olivier Niel, Élisabeth Cassuto, Aymeric Dallocchio, Etienne Bérard, Vincent Guigonis, Véronique Frémeaux-Bacchi, Marie-Christine Thouret, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and RUIZ, Caroline

Subjects
Nephrology, medicine.medical_specialty, Adolescent, MESH: Glomerulonephritis, Membranous, 030232 urology & nephrology, Glomerulonephritis, Membranous, 03 medical and health sciences, 0302 clinical medicine, MESH: Child, Internal medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Membranoproliferative glomerulonephritis, medicine, Humans, Dense Deposit Disease, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, MESH: Adolescent, Complement C3 Nephritic Factor, 0303 health sciences, MESH: Humans, Proteinuria, Complement component 3, business.industry, MESH: Complement C3 Nephritic Factor, Autoantibody, Glomerulonephritis, medicine.disease, 3. Good health, Transplantation, Pediatrics, Perinatology and Child Health, Immunology, Female, medicine.symptom, business, MESH: Female
Abstract

International audience; C3 nephritic factor (C3NeF) has been described in association with membranoproliferative glomerulonephritis and is involved in 80 % of cases of dense deposit disease. C3NeF is an immunoglobulin G (IgG) autoantibody which binds to the complement component 3 (C3) convertase C3bBb, thereby inhibiting its decay and leading to massive C3 cleavage. Commonly associated with C3NeF are low C3 levels, decreased total haemolytic complement (CH50) and normal C4 levels. C3NeF patients often present with proteinuria, haematuria and high blood pressure. Evolution to end-stage renal disease is common. Treatment consists of steroids and/or immunosuppressants, with variable efficiency. Renal transplantation is marked by histological recurrence, leading to higher rates of allograft loss. We report C3NeF in association with membranous glomerulonephritis type 3-4 in two unrelated children. We also demonstrate that, under adequate immunosuppressive therapy, proteinuria is significantly lowered, blood pressure is kept within normal range and long-term renal function remains normal. C3NeF can be associated with membranous glomerulonephritis in children. Clinical presentation is mild, and mid-term outcome is favourable under adequate therapy. However, complement anomalies persist for several years.

Published
2014
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5. Phospholipase A2 Receptor-Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency

Author

John Rendu, Chantal Dumestre-Pérard, Julien Fauré, Hanna Debiec, Stéphane Bally, Pierre Ronco, Denise Ponard, Frédérique Dijoud, Service de néphrologie - dialyse [Centre hospitalier Métropole Savoie - Chambéry], Centre Hospitalier Métropole Savoie [Chambéry], Laboratoire d'immunohistochimie, CHU Grenoble-Hôpital Michallon, Groupe Hospitalier Est, Centre de Pathologie Est, Hospices Civils de Lyon (HCL), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Departement de Biochimie,Toxicologie et Pharmacologie, CHU Grenoble, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation

Subjects
0301 basic medicine, Adult, Male, MESH: Glomerulonephritis, Membranous, glomerular disease, 030232 urology & nephrology, chemical and pharmacologic phenomena, Biology, Complement factor B, Glomerulonephritis, Membranous, Mannose-Binding Lectin, 03 medical and health sciences, 0302 clinical medicine, Membranous nephropathy, MESH: Receptors, Phospholipase A2, medicine, Humans, complement, Mannan-binding lectin, MESH: Humans, Receptors, Phospholipase A2, membranous nephropathy, MESH: Adult, General Medicine, MBL deficiency, medicine.disease, Molecular biology, MESH: Male, MESH: Mannose-Binding Lectin, 3. Good health, Complement system, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, Nephrology, Lectin pathway, immunohistochemistry, Alternative complement pathway, Properdin, Brief Communications
Abstract

International audience; Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against phospholipase A2 receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2.

Published
2015
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6. Allo-Immune Membranous Nephropathy and Recombinant Aryl Sulfatase Replacement Therapy: A Need for Tolerance Induction Therapy

Author

Laure-Hélène Noël, Vassili Valayannopoulos, Pierre Ronco, Niaudet P, Olivia Boyer, Patrice Callard, Pascale de Lonlay, Hanna Debiec, Hélène Sarda, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence pour les maladies métaboliques héréditaires [CHU Necker Enfants Malades - AP-HP], 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), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pédiatrie [CH René Dubos, Pontoise], Centre Hospitalier René Dubos [Pontoise], Research is supported by European Research Council Grant ERC-2012-ADG_20120314 (Grant Agreement 322947), Agence Nationale pour la Recherche Programme Blanc SVSE1 (2012) Decision ANR-12-BSE1-0002-01, Fondation pour la Recherche Médicale Equipe FRM 2012 grant, and 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases)., European Project: 322947,EC:FP7:ERC,ERC-2012-ADG_20120314,OSAI(2013), European Project: 305608,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EURENOMICS(2012), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie pathologique [CHU Necker], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie, Hopital Réné Dubos-CH Pontoise, European Research Council Grant ERC-2012-ADG_20120314 (Grant Agreement 322947), Agence Nationale pour la Recherche Programme Blanc SVSE1 (2012) Decision ANR-12-BSE1-0002-01, Fondation pour la Recherche Médicale Equipe FRM 2012 grant, and 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare KidneyDiseases)., Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [CHU Tenon], RONCO, Pierre, Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI) - OSAI - - EC:FP7:ERC2013-05-01 - 2018-04-30 - 322947 - VALID, European Consortium for High-Throughput Research in Rare Kidney Diseases - EURENOMICS - - EC:FP7:HEALTH2012-10-01 - 2017-09-30 - 305608 - VALID, Service de Département de Néphrologie = Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service de néphrologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, N-Acetylgalactosamine-4-Sulfatase, Mucopolysaccharidosis type VI, MESH: Glomerulonephritis, Membranous, MESH : Child, Preschool, MESH : N-Acetylgalactosamine-4-Sulfatase, Gastroenterology, Glomerulonephritis, Membranous, MESH: Recombinant Proteins, 0302 clinical medicine, Isoantibodies, Medicine, MESH : Glomerulonephritis, Membranous, MESH: Enzyme Replacement Therapy, 0303 health sciences, Proteinuria, Mucopolysaccharidosis VI, MESH : Enzyme Replacement Therapy, MESH : Immune Tolerance, Glomerulonephritis, General Medicine, Enzyme replacement therapy, Recombinant Proteins, 3. Good health, Tolerance induction, Nephrology, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine.symptom, Brief Communications, medicine.medical_specialty, MESH: Immune Tolerance, MESH: Mucopolysaccharidosis VI, MESH : Recombinant Proteins, MESH : Male, MESH : Isoantibodies, MESH: N-Acetylgalactosamine-4-Sulfatase, Nephropathy, 03 medical and health sciences, Membranous nephropathy, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Immune Tolerance, Humans, Enzyme Replacement Therapy, 030304 developmental biology, MESH: Humans, business.industry, MESH : Humans, MESH: Child, Preschool, medicine.disease, MESH: Isoantibodies, MESH: Male, MESH : Mucopolysaccharidosis VI, Immunology, business, Nephrotic syndrome, 030217 neurology & neurosurgery
Abstract

International audience; Nephrotic syndrome was reported in a highly-sensitized patient receiving enzyme replacement therapy (ERT) for Pompe disease, but the prevalence of ERT-induced renal complications and mechanisms to facilitate readministration of ERT in these patients remain unexplored. This work identifies a new antigen responsible for secondary membranous nephropathy (MN) in a patient with mucopolysaccharidosis type VI caused by aryl sulfatase B (ASB) deficiency. ERT (recombinant human ASB [rhASB]; 1 mg/kg per week) started at the age of 4 years led to a high anti-rhASB titer and dramatically improved clinical manifestations. However, 16 months later, the patient suddenly developed nephrotic syndrome resistant to steroid therapy 1 week after orthopedic surgery. Examination of the kidney biopsy specimen revealed glomerular deposition of IgG (mostly IgG4, C3, and C5b-9) in a granular pattern typical of MN. Double immunofluorescence staining showed that subepithelial granular deposits contained rhASB colocalized with IgG. Ig eluted from the patient's biopsy specimen reacted specifically with rhASB. On discontinuation of ERT, proteinuria progressively decreased, but the patient's clinical condition markedly deteriorated. Induction of tolerance to rhASB was initiated by coadministration of low-dose corticosteroids, rituximab, intravenous Igs, and oral methotrexate. ERT was resumed 8 weeks after starting immunosuppressive therapy without inducing a rebound of antibody titer or an increase in proteinuria. We conclude that the allo-immune response to the recombinant rhASB caused the nephropathy. Considering the critical requirement for ERT in patients with such enzyme deficiencies, immune tolerance induction should be advocated in the patients with allo-immune MN.

Published
2014
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7. [IgG4-related disease and renal and urological involvement]

Author

Zaidan, Mohamad, Ebbo, Mikael, Brochériou, Isabelle, Ronco, Pierre, Schleinitz, Nicolas, Boffa, Jean-Jacques, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d'anatomie pathologique [CHU Tenon], Aix Marseille Université (AMU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), RONCO, Pierre, Service de Département de Néphrologie = Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service d'Anatomie et cytologie pathologiques [CHU Tenon]

Subjects
MESH: Glomerulonephritis, Membranous, pancreatitis, Kidney, Glomerulonephritis, Membranous, MESH: Retroperitoneal Fibrosis, MESH: Aortitis, aneurysms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Tubulointerstitial nephritis, IgG4-related disease, Glucocorticoids, IgG4, MESH: Immunoglobulin G, MESH: Humans, Aortitis, Aortic, MESH: Kidney, Retroperitoneal fibrosis, Aortitis Autoimmune, Aortic Aneurysm, Prostatitis, MESH: Aortic Aneurysm, Immunoglobulin G, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Nephritis, Interstitial, MESH: Glucocorticoids, MESH: Nephritis, Interstitial
Abstract

International audience; Hyper-IgG4 syndrome, or IgG4-related disease, is an emerging disorder, involving one or more organ(s), and characterized by "storiform" fibrosis and inflammatory lesions with a predominance of IgG4+ plasma cells and increased IgG4 serum levels. Since the first report of auto-immune pancreatitis, numerous organ lesions have been reported and have been found to occur in a same patient including: sialadenitis, dacryoadenitis, lymphadenopathy, liver and biliary tract involvement, and renal and retroperitoneal lesions. Renal involvement was first described in 2004 and usually presents as functional and/or morphological abnormalities. In most cases, renal pathological analysis reveals tubulointerstitial nephritis that is rarely associated with glomerular lesions. Retroperitoneal fibrosis is also a typical feature that may be associated with periaortitis or inflammatory abdominal aortic aneurysm. First line treatment is based on corticosteroid therapy. Short-term outcome is usually favorable. However, patients should be carefully monitored for relapses and long-term complications. Although the multiple organ lesions share common clinical, biological, radiological and pathological features, no consensus diagnostic criteria have yet been validated for IgG4-related disease. Ruling out differential diagnoses is thus mandatory. Our literature review provides nephrologists, urologists and pathologists with key elements that will help in the early diagnosis and proper management of this new and emerging disorder.

Published
2012
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8. Recurrent membranous nephropathy in an allograft caused by IgG3κ targeting the PLA2 receptor

Author

Michel Godin, Pierre Aucouturier, Arnaud François, Catherine Johanet, Hanna Debiec, Sophie Ferlicot, Pierre Ronco, Dominique Guerrot, M. Hanoy, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Nouvelles Cibles Pharmacologiques de la Protection Endothéliale et de l'Insuffisance Cardiaque (EnVI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Service de pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service immunologie, Centre de Recherche Saint-Antoine (UMRS893), The work was supported by grants from Fondation pour la Recherche Médicale (Equipe FRM2012) and by grant from Agence Nationale pour la Recherche (ANR-07-hysio-016-01)., RONCO, Pierre, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Pathology, medicine.medical_specialty, Glomerular deposits, MESH: Glomerulonephritis, Membranous, 030232 urology & nephrology, Biology, Brief Communication, Glomerulonephritis, Membranous, MESH: Kidney Transplantation, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, Membranous nephropathy, Recurrence, MESH: Postoperative Complications, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biopsy, medicine, MESH: Receptors, Phospholipase A2, MESH: Transplantation, Homologous, Humans, Transplantation, Homologous, Kidney transplantation, 030304 developmental biology, MESH: Immunoglobulin G, 0303 health sciences, Proteinuria, MESH: Humans, MESH: Middle Aged, medicine.diagnostic_test, Receptors, Phospholipase A2, Glomerulonephritis, General Medicine, Middle Aged, medicine.disease, Kidney Transplantation, MESH: Male, 3. Good health, MESH: Recurrence, Transplantation, Nephrology, Immunoglobulin G, Monoclonal, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine.symptom
Abstract

International audience; Up to 80% of patients with idiopathic membranous nephropathy have non-complement-fixing IgG4 autoantibodies to the phospholipase A2 receptor (PLA2R). Membranous nephropathy recurs in approximately 40% of patients after kidney transplantation, but the mechanism is unknown. Here, we describe a patient with recurrent membranous nephropathy 13 days after kidney transplantation whose graft biopsy specimen showed granular staining for C3, C5b-9, C1q, and IgG3κ; electron microscopy revealed subepithelial nonorganized deposits. A search for hematologic disorders was negative. Retrospective evaluation of a biopsy sample from the native kidney revealed a similar pattern: monotypic IgG3κ deposits together with C3, C1q, and C5b-9. Glomerular deposits contained PLA2R in both the graft and the native kidney, suggesting that the recurrence was the result of circulating anti-PLA2R antibodies binding to PLA2R antigen expressed on donor podocytes. Confocal analysis of anti-PLA2R and antihuman IgG3 showed co-localization, and the patient had IgG3κ-restricted circulating anti-PLA2R antibodies. Treatment with rituximab stabilized both proteinuria and serum creatinine, and circulating anti-PLA2R became undetectable. In summary, this case of recurrent membranous nephropathy in a graft suggests that circulating monoclonal anti-PLA2R IgG3κ caused the disease and activated complement by the classic pathway.

Published
2012
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9. [Idiopathic and secondary membranous nephropathies]

Author

Pierre, Ronco, Hanna, Debiec, RONCO, Pierre, Remodelage et Reparation du Tissu Renal, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, MESH: Glomerulonephritis, Membranous, Glomerulonephritis, Membranous, Polymorphism, Single Nucleotide, Antibodies, HLA-DQ alpha-Chains, White People, MESH: Child, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: HLA-DQ alpha-Chains, MESH: Receptors, Phospholipase A2, Humans, Genetic Predisposition to Disease, Child, MESH: Age Factors, MESH: Humans, MESH: Neprilysin, Receptors, Phospholipase A2, MESH: Polymorphism, Single Nucleotide, MESH: Antibodies, Age Factors, MESH: Genetic Predisposition to Disease, Serum Albumin, Bovine, MESH: Adult, MESH: European Continental Ancestry Group, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neprilysin, MESH: Serum Albumin, Bovine
Abstract

International audience; Antibodies to neutral endopeptidase, a podocyte protein, are responsible for rare alloimmune neonatal membranous nephropathy that develops in children from neutral endopeptidase-deficient mothers. Neutral endopeptidase was the first podocyte antigen described in human membranous nephropathy. PLA2R1, the type-M receptor of soluble phospholipase A2, is a major target antigen in so-called idiopathic membranous nephropathy in adults. Antibodies to PLA2R1 are detected in 60 to 80% of patients before immunosuppressive treatment, and are only occasionally found in secondary membranous nephropathy. To date, they have not been detected in other pathological conditions and in healthy individuals. PLA2R1 and HLA-DQA1 gene variants defined by single nucleotide polymorphisms are strongly associated with idiopathic membranous nephropathy in patients of white ancestry, and can thus be considered as predisposing genes. In addition to their diagnostic value, anti-PLA2R1 antibodies can be used to monitor treatment. Immunization against cationic bovine serum albumin is a cause of early childhood membranous nephropathy. This finding points to a possible role of food and environmental antigens in membranous nephropathy. The newly identified antigen-antibody systems should be considered as molecular signatures challenging the uniform histological definition and having a major impact on patient care in a near future.

Published
2012
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10. Autoantibodies specific for the phospholipase A2 receptor in recurrent and De Novo membranous nephropathy

Author

Laurent Mesnard, Eric Rondeau, Christiane Mousson, G. Dautin, Pierre Ronco, Hanna Debiec, Chantal Jouanneau, L. Martin, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Urgences Néphrologiques & Transplantation Rénale, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne ( UB ), Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), EFS Bourgogne Franche-Comté ( EFS-BFC ), Etablissement Français du Sang (EFS), Service de néphrologie (CHU de Dijon), Agence de la Biomédecine, Fondation pour la Recherche Médicale and 'Association pour l'Utilisation du Rein Artificiel' (AURA). H.D. is the recipient of a 'Contrat d'Interface' from Assistance Publique-Hôpitaux de Paris., Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Bourgogne (UB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Etablissement Français du Sang de Bourgogne Franche-Comté (site de Dijon) (EFS BFC (site de Dijon)), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), RONCO, Pierre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)

Subjects
Male, MESH : Recurrence, MESH : DNA, Complementary, MESH: Glomerulonephritis, Membranous, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Glomerulonephritis, Membranous, 0302 clinical medicine, Recurrence, [ SHS.INFO ] Humanities and Social Sciences/Library and information sciences, Immunology and Allergy, Medicine, MESH: Autoantibodies, MESH : Fluorescent Antibody Technique, Direct, Pharmacology (medical), MESH : Female, MESH : Glomerulonephritis, Membranous, Receptor, MESH: Middle Aged, biology, MESH : Receptors, Phospholipase A2, Glomerulonephritis, Middle Aged, respiratory system, MESH : Adult, 3. Good health, Fluorescent Antibody Technique, Direct, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, lipids (amino acids, peptides, and proteins), De novo, Antibody, MESH: Fluorescent Antibody Technique, Direct, Adult, DNA, Complementary, [SHS.INFO]Humanities and Social Sciences/Library and information sciences, MESH : Male, macromolecular substances, [SHS.INFO] Humanities and Social Sciences/Library and information sciences, 03 medical and health sciences, recurrent, Antigen, Membranous nephropathy, stomatognathic system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH : Autoantibodies, MESH: Receptors, Phospholipase A2, Humans, MESH : Middle Aged, Direct fluorescent antibody, PLA2R1, Autoantibodies, Transplantation, MESH: Humans, business.industry, Receptors, Phospholipase A2, MESH : Humans, Autoantibody, membranous nephropathy, MESH: Adult, MESH: DNA, Complementary, medicine.disease, equipment and supplies, MESH: Male, MESH: Recurrence, Immunology, biology.protein, business, MESH: Female
Abstract

International audience; Recent findings in idiopathic membranous nephropathy (MN) suggest that in most patients, the disease is because of anti-phospholipase A(2) receptor (PLA(2) R1) autoantibodies. Our aim was to analyze the prevalence and significance of anti-PLA(2) R1 antibodies in recurrent and de novo MN after transplantation. We assessed circulating PLA(2) R1 autoantibodies by a direct immunofluorescence assay based on human embryonic kidney cells transfected with a PLA(2) R1 cDNA, and the presence of PLA(2) R1 antigen in immune deposits. We showed that PLA(2) R1 was involved in 5 of 10 patients with recurrent MN, but in none of the 9 patients with de novo MN. We also showed a marked heterogeneity in the kinetics and titers of anti-PLA(2) R1, which may relate to different pathogenic potential. We provide evidence that some patients with PLA(2) R1-related idiopathic MN and anti-PLA(2) R1 antibodies at the time of transplantation will not develop recurrence. Because PLA(2) R1 autoantibody was not always associated with recurrence, its predictive value should be carefully analyzed in prospective studies.

Published
2011
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11. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy

Author

Laurence H. Beck, Timothy D. Cummins, David J. Salant, Ramon G. Bonegio, David W. Powell, Jon B. Klein, Gérard Lambeau, David M. Beck, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), School of Medicine, and University of Louisville

Subjects
Pathology, medicine.medical_specialty, MESH: Chi-Square Distribution, MESH: Epitopes, Glomerular deposits, Blotting, Western, Kidney Glomerulus, MESH: Glomerulonephritis, Membranous, 030232 urology & nephrology, Monospecific antibody, Glomerulonephritis, Membranous, Article, Immunoglobulin G, Mass Spectrometry, Nephropathy, 03 medical and health sciences, Heymann Nephritis, Epitopes, 0302 clinical medicine, Membranous nephropathy, medicine, MESH: Receptors, Phospholipase A2, Humans, MESH: Autoantibodies, MESH: Blotting, Western, 030304 developmental biology, Autoantibodies, MESH: Immunoglobulin G, MESH: Mass Spectrometry, 0303 health sciences, Chi-Square Distribution, MESH: Humans, biology, business.industry, Receptors, Phospholipase A2, Autoantibody, Glomerulonephritis, MESH: Kidney Glomerulus, General Medicine, medicine.disease, 3. Good health, Immunology, biology.protein, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; BACKGROUND: Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown. METHODS: We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody. RESULTS: Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A(2) receptor (PLA(2)R). Reactive serum specimens recognized recombinant PLA(2)R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA(2)R antibody. Anti-PLA(2)R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA(2)R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA(2)R. CONCLUSIONS: A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA(2)R. PLA(2)R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA(2)R is a major antigen in this disease.

Published
2009
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12. The M-type receptor PLA2R regulates senescence through the p53 pathway

Author

Arnaud Augert, Christine Payré, Yvan de Launoit, Gérard Lambeau, Jesús Gil, David Bernard, Institut de Biologie de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Cell Proliferation Group, and Imperial College London

Subjects
MESH: Signal Transduction, MESH: Chi-Square Distribution, MESH: Glomerulonephritis, Membranous, medicine.disease_cause, Biochemistry, MESH: Down-Regulation, 0302 clinical medicine, MESH: Autoantibodies, MESH: Animals, MESH: Tumor Suppressor Protein p53, Cellular Senescence, MESH: Immunoglobulin G, 0303 health sciences, Gene knockdown, MESH: Reactive Oxygen Species, Cell biology, MESH: Cell Aging, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Signal transduction, Cell aging, Signal Transduction, Senescence, MESH: Epitopes, Scientific Report, Down-Regulation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cell Line, 03 medical and health sciences, Genetics, medicine, MESH: Receptors, Phospholipase A2, MESH: Blotting, Western, Animals, Humans, Molecular Biology, 030304 developmental biology, MESH: Mass Spectrometry, MESH: Humans, Receptors, Phospholipase A2, MESH: Kidney Glomerulus, Fibroblasts, MESH: Gene Knockdown Techniques, Telomere, MESH: Cell Line, MESH: Fibroblasts, Cancer research, Ectopic expression, Tumor Suppressor Protein p53, Carcinogenesis, Reactive Oxygen Species, Genetic screen
Abstract

International audience; Senescence is a stable proliferative arrest induced by various stresses such as telomere erosion, oncogenic or oxidative stress. Compelling evidence suggests that it acts as a barrier against tumour development. Describing new mechanisms that favour an escape from senescence can thus reveal new insights into tumorigenesis. To identify new genes controlling the senescence programme, we performed a loss-of-function genetic screen in primary human fibroblasts. We report that knockdown of the M-type receptor PLA2R (phospholipase A2 receptor) prevents the onset of replicative senescence and diminishes stress-induced senescence. Interestingly, expression of PLA2R increases during replicative senescence, and its ectopic expression results in premature senescence. We show that PLA2R regulates senescence in a reactive oxygen species-DNA damage-p53-dependent manner. Taken together, our study identifies PLA2R as a potential new tumour suppressor gene crucial in the induction of cellular senescence through the activation of the p53 pathway.

Published
2008
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