JCI - Kallikrein genes are associated with lupus and glomerular basement membrane–specific antibody

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 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

Published in Volume 119, Issue 4

J Clin Invest. 2009; 119(4):911–923 doi:10.1172/JCI36728

Abstract | Full text | PDF | Supplemental material

I mmune-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.

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Figure 5

Sequence analysis of the 5′-regulatory regions of Klk genes reveals nucleotide polymorphisms that distinguish the AIGN-sensitive strains from the control strains.

When 2 kb of the 5′-regulatory regions of Klk1, Klk1b3, Klk1b5, Klk1b26, and Klk1b27 from the indicated strains were sequenced, several SNPs/deletions were identified, as detailed in Table 2 (GenBank accession numbers EU597301–EU597324). (A) Phylogenetic analysis revealed the sequence of the AIGN-sensitive strains to be closely related, compared with the sequences of the 2 control strains. Bars represent the fraction of sequence variation. (B) Part of the nucleotide sequence of the Klk1b3 promoter (up to 200 bp upstream of transcription start site) from the different study strains indicated. Note that the B6.Sle3^z strain bears the NZW allele at Klk. (C) One kilobase of the promoter region of Klk1b3 from both BALB/c and DBA/1 strains was inserted into the pGL4 luciferase vector and transfected into COS-7 cells, and luciferase activity was assayed 24 hours later, as detailed in Methods. Each bar represents the median of triplicate values, and the error bars denote SD. Cells transfected with vectors carrying the BALB/c-derived Klk1b3 promoter showed significantly increased luciferase activity compared with cells with vectors bearing the DBA/1 promoter or vector alone (P < 0.01). Similar differences were noted when the B6 Klk1b3 promoter was compared with the B6.Sle3^z Klk1b3 promoter (data not shown).