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.
Authors
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 Barizzone, Gian 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, The Profile Study Group, The Italian Collaborative Group, The German Collaborative Group, The Spanish Collaborative Group, The Argentinian Collaborative Group, The SLEGEN Consortium, Edward K. Wakeland, Marta E. Alarcón-Riquelme, Chandra Mohan
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