title: Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.
abstract: IgA nephropathy (IgAN) is a common cause of renal failure worldwide. Treatment is limited because of a complex pathogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium. IgA receptor abnormalities are implicated, including circulating IgA-soluble CD89 (sCD89) complexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1). Herein, we show that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposits of IgA1-sCD89 complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits. sCD89 was also detected in patient and mouse mesangium. IgA1 deposition involved a direct binding of sCD89 to mesangial TfR1 resulting in TfR1 up-regulation. sCD89-TfR1 interaction induced mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression. In the absence of TGase2, IgA1-sCD89 deposits were dramatically impaired. These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed for disease development. They demonstrate that TGase2 is responsible for a pathogenic amplification loop facilitating IgA1-sCD89 deposition and mesangial cell activation, thus identifying TGase2 as a target for therapeutic intervention in this disease.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 699, Paris 75870, France.
authors.forename: Laureline
authors.initials: L
authors.lastname: Berthelot
authors.forename: Christina
authors.initials: C
authors.lastname: Papista
authors.forename: Thiago T
authors.initials: TT
authors.lastname: Maciel
authors.forename: Martine
authors.initials: M
authors.lastname: Biarnes-Pelicot
authors.forename: Emilie
authors.initials: E
authors.lastname: Tissandie
authors.forename: Pamela H M
authors.initials: PH
authors.lastname: Wang
authors.forename: Houda
authors.initials: H
authors.lastname: Tamouza
authors.forename: Agnès
authors.initials: A
authors.lastname: Jamin
authors.forename: Julie
authors.initials: J
authors.lastname: Bex-Coudrat
authors.forename: Aurelie
authors.initials: A
authors.lastname: Gestin
authors.forename: Ahmed
authors.initials: A
authors.lastname: Boumediene
authors.forename: Michelle
authors.initials: M
authors.lastname: Arcos-Fajardo
authors.forename: Patrick
authors.initials: P
authors.lastname: England
authors.forename: Evangéline
authors.initials: E
authors.lastname: Pillebout
authors.forename: Francine
authors.initials: F
authors.lastname: Walker
authors.forename: Eric
authors.initials: E
authors.lastname: Daugas
authors.forename: François
authors.initials: F
authors.lastname: Vrtosvnik
authors.forename: Martin
authors.initials: M
authors.lastname: Flamant
authors.forename: Marc
authors.initials: M
authors.lastname: Benhamou
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D005922:Glomerulonephritis, IGA / Q000209:etiology*; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011961:Receptors, Fc / Q000502:physiology*; D011990:Receptors, Transferrin / Q000378:metabolism; D011503:Transglutaminases / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C036832:Fc(alpha) receptor; C045281:IgA receptor; D007070:Immunoglobulin A; D011961:Receptors, Fc; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins