Increased Goodpasture Antigen-Binding Protein Expression Induces Type IV Collagen Disorganization and Deposit of Immunoglobulin A in Glomerular Basement Membrane

Fernando Revert^*, Ramón Merino, Carlos Monteagudo, Jesús Macias^*, Amando Peydró, Javier Alcácer, Pedro Muniesa^¶, Regina Marquina^||, Mario Blanco^*, Marcos Iglesias^||, Francisco Revert-Ros^*, Jesús Merino^|| and Juan Saus^***

From the Centro de Investigación Príncipe Felipe,^* Valencia; the Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria-IDICAN, and the Departamento de Biología Molecular,|| Unidad Asociada al Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Científicas, Universidad de Cantabria, Santander; the Departamentos de Patología and Bioquímica y Biología Molecular,^*^* Universidad de Valencia, Valencia; the Servicio de Anatomía Patológica, Hospital Quirón de Valencia, Valencia; and the Departamento de Anatomía, Embriología, y Genética,^¶ Universidad de Zaragoza, Zaragoza, Spain

Increased expression of Goodpasture antigen-binding protein(GPBP), a protein that binds and phosphorylates basement membranecollagen, has been associated with immune complex-mediated pathogenesis.However, recent reports have questioned this biological functionand proposed that GPBP serves as a cytosolic ceramide transporter(CERT_L). Thus, the role of GPBP in vivo remains unknown. NewZealand White (NZW) mice are considered healthy animals althoughthey convey a genetic predisposition for immune complex-mediatedglomerulonephritis. Here we show that NZW mice developed age-dependentlupus-prone autoimmune response and immune complex-mediatedglomerulonephritis characterized by elevated GPBP, glomerularbasement membrane (GBM) collagen disorganization and expansion,and deposits of IgA on disrupted GBM. Transgenic overexpressionof human GPBP (hGPBP) in non-lupus-prone mice triggered similarglomerular abnormalities including deposits of IgA on a capillaryGBM that underwent dissociation, in the absence of an evidentautoimmune response. We provide in vivo evidence that GPBP regulatesGBM collagen organization and its elevated expression causesdissociation and subsequent accumulation of IgA on the GBM.Finally, we describe a previously unrecognized pathogenic mechanismthat may be relevant in human primary immune complex-mediatedglomerulonephritis.