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 2

The differential renal expression of Klk in the AIGN-sensitive versus control strains was confirmed at the protein level.

BALB/c, DBA1, and 129/SvJ mice were subjected to AIGN. (A) Fourteen days after anti-GBM challenge, kallikrein protein expression was assayed in the renal cortex by Western blotting, using a rabbit anti–mouse Klk1 Ab. The bar chart below (n = 3 mice per group) shows Klk expression normalized to GAPDH (AU). *P < 0.001, compared with all other study groups. (B) Twenty-four-hour urine samples collected from these mice on days 0, 10, and 14 after anti-GBM insult were also assayed for kallikrein enzymatic activity, using the synthetic chromogenic substrate HD-Val-Leu-Arg-pNA (S-2266), as detailed in Methods. Similar differences in renal and urinary kallikrein levels were noted between B6 and B6.Sle3^z mice (data not shown). Error bars in A denote SD. In B, each dot represents data from a single mouse, and the horizontal bars denote arithmetic group means.