title: Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease.
abstract: Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN.
authors.affiliation: National Institute for Health and Medical Research (INSERM), Mixed Research Unit S1155, Tenon Hospital, Paris, France; Sorbonne University, Pierre and Marie Curie University (University of Paris 6), Paris, France; and.
authors.forename: Fala
authors.initials: F
authors.lastname: El Machhour
authors.affiliation: National Institute for Health and Medical Research (INSERM), Mixed Research Unit S1155, Tenon Hospital, Paris, France;
authors.forename: Zela
authors.initials: Z
authors.lastname: Keuylian
authors.affiliation: National Institute for Health and Medical Research (INSERM), Mixed Research Unit S1155, Tenon Hospital, Paris, France;
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Kavvadas
authors.affiliation: National Institute for Health and Medical Research (INSERM), Mixed Research Unit S1155, Tenon Hospital, Paris, France; Sorbonne University, Pierre and Marie Curie University (University of Paris 6), Paris, France; and Department of Physiology, Saint-Antoine Hospital, Public Hospital Network of Paris, Paris, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dussaule
authors.affiliation: National Institute for Health and Medical Research (INSERM), Mixed Research Unit S1155, Tenon Hospital, Paris, France; Sorbonne University, Pierre and Marie Curie University (University of Paris 6), Paris, France; and christos.chatziantoniou@upmc.fr.
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D011507:Proteinuria / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D012016:Reference Values; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000473:pathology; D012756:Sheep; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C499373:Notch3 protein, mouse; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: GN; anti-GBM disease; chronic renal disease; proteinuria