Published online before print October 4, 2007

This Article Full Text (Rapid PDF) Supplemental Material All Versions of this Article: ajpath.2007.070205v1 171/5/1419    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Revert, F. Articles by Saus, J. Search for Related Content PubMed PubMed Citation Articles by Revert, F. Articles by Saus, J.

Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070205

Accepted for publication August 3, 2007.

Article

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

^@ To whom correspondence should be addressed. E-mail: jsaus{at}cipf.es.

	Abstract

Increased expression of Goodpasture antigen-binding protein (GPBP), a protein that binds and phosphorylates basement membrane collagen, has been associated with immune complex-mediated pathogenesis. However, recent reports have questioned this biological function and proposed that GPBP serves as a cytosolic ceramide transporter (CERT_L). Thus, the role of GPBP in vivo remains unknown. New Zealand White (NZW) mice are considered healthy animals although they convey a genetic predisposition for immune complex-mediated glomerulonephritis. Here we show that NZW mice developed age-dependent lupus-prone autoimmune response and immune complex-mediated glomerulonephritis characterized by elevated GPBP, glomerular basement membrane (GBM) collagen disorganization and expansion, and deposits of IgA on disrupted GBM. Transgenic overexpression of human GPBP (hGPBP) in non-lupus-prone mice triggered similar glomerular abnormalities including deposits of IgA on a capillary GBM that underwent dissociation, in the absence of an evident autoimmune response. We provide in vivo evidence that GPBP regulates GBM collagen organization and its elevated expression causes dissociation and subsequent accumulation of IgA on the GBM. Finally, we describe a previously unrecognized pathogenic mechanism that may be relevant in human primary immune complex-mediated glomerulonephritis.