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 4

The Sle3^z locus, particularly the Sle3^z_157–158 subinterval on chromosome 7, may be responsible for the reduced Klk and enhanced nephritis susceptibility seen in NZW mice.

(A) Shown are the Sle3^z lupus susceptibility interval on chromosome 7 (Chr. 7; black denotes the interval derived from NZM2410/NZW; gray denotes B6 origin); the 4-Mb subinterval spanning D7mit157 to D7mit158 (denoted by the dashed line on right); and the cluster of Klk genes harbored within the indicated subinterval. The numbers on the right refer to the positions of respective microsatellite markers (e.g., 157 represents D7mit157). Shown also are the 24-hour urine protein excretion profiles (B), blood urea nitrogen (BUN) (C), GN pathology score (D), and renal Klk message levels (E), 14 days after anti-GBM challenge of B6, B6.Sle3^z, and B6.Sle3^z_157–158 congenics (n = 5 each). The data shown in B–D were reproduced in at least 2 additional experiments. In the second study, for example, the B6.Sle3^z_157–158 congenics exhibited significantly higher 24-hour protein levels in urine (P < 0.045) and GN score (P < 0.013) and more severe tubulo-intersitial disease (P < 0.001), compared with the B6 control (data not plotted). All statistical comparisons were made with the respective B6 controls, using the Mann-Whitney U test. In B–D, each dot represents data from a single mouse, and the horizontal bars denote arithmetic group means. Error bars in E denote SD.