Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans

Kui Liu, Quan Zhen Li, Angelica M. Delgado-Vega, Anna Karin Abelson, Elena Sánchez, Jennifer A. Kelly, Li Li, Yang Liu, Jinchun Zhou, Mei Yan, Qiu Ye, Shenxi Liu, Chun Xie, Xin J. Zhou, Sharon A. Chung, Bernardo Pons-Estel, Torsten Witte, Enrique De Ramón, Sang Cheol Bae, Nadia BarizzoneGian Domenico Sebastiani, Joan T. Merrill, Peter K. Gregersen, Gary G. Gilkeson, Robert P. Kimberly, Timothy J. Vyse, Il Kim, Sandra D'Alfonso, Javier Martin, John B. Harley, Lindsey A. Criswell, Edward K. Wakeland, Marta E. Alarcón-Riquelme, Chandra Mohan, Maria Giovanna Danieli, Mauro Galeazzi, Patrizia Rovere Querini, Sergio Migliaresi, Hugo R. Scherbarth, Jorge A. Lopez, Estela L. Motta, Susana Gamron, Cristina Drenkard, Emilia Menso, Alberto Allievi, Guillermo A. Tate, José L. Presas, Simon A. Palatnik, Marcelo Abdala, Mariela Bearzotti, Alejandro Alvarellos, Francisco Caeiro, Ana Bertoli, Sergio Paira, Susana Roverano, Cesar E. Graf, Estela Bertero, Cesar Caprarulo, Griselda Buchanan, Carolina Guillerón, Sebastian Grimaudo, Jorge Manni, Luis J. Catoggio, Enrique R. Soriano, Carlos D. Santos, Cristina Prigione, Fernando A. Ramos, Sandra M. Navarro, Guillermo A. Berbotto, Marisa Jorfen, Elisa J. Romero, Mercedes A. Garcia, Juan C. Marcos, Ana I. Marcos, Carlos E. Perandones, Alicia Eimon, Cristina G. Battagliotti, K. Armadi-Simab, Wolfgang L. Gross, Erika Gromnica-Ihle, Hans Hartmut Peter, Karin Manger, Sebastian Schnarr, Henning Zeidler, Reinhold E. Schmidt, Norberto Ortego, José L. Callejas, Juan Jiménez-Alonso, Mario Sabio, Julio Sánchez-Román, Francisco J. Garcia-Hernandez, Mayte Camps, Miguel Angel López-Nevot, Maria F. González-Escribano, Carl Langefeld, Betty Tsao, Chaim Jacob

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Abstract

Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that may be responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family, which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms, some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.

Original languageEnglish (US)
Pages (from-to)911-923
Number of pages13
JournalJournal of Clinical Investigation
Volume119
Issue number4
DOIs
StatePublished - Apr 1 2009

ASJC Scopus subject areas

  • Medicine(all)

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    Liu, K., Li, Q. Z., Delgado-Vega, A. M., Abelson, A. K., Sánchez, E., Kelly, J. A., Li, L., Liu, Y., Zhou, J., Yan, M., Ye, Q., Liu, S., Xie, C., Zhou, X. J., Chung, S. A., Pons-Estel, B., Witte, T., De Ramón, E., Bae, S. C., ... Jacob, C. (2009). Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans. Journal of Clinical Investigation, 119(4), 911-923. https://doi.org/10.1172/JCI36728