title: Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans.
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 maybe 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.affiliation: Department of Immunology and Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8884, USA.
authors.forename: Kui
authors.initials: K
authors.lastname: Liu
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Delgado-Vega
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Abelson
authors.forename: Elena
authors.initials: E
authors.lastname: Sánchez
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Jinchun
authors.initials: J
authors.lastname: Zhou
authors.forename: Mei
authors.initials: M
authors.lastname: Yan
authors.forename: Qiu
authors.initials: Q
authors.lastname: Ye
authors.forename: Shenxi
authors.initials: S
authors.lastname: Liu
authors.forename: Chun
authors.initials: C
authors.lastname: Xie
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Chung
authors.forename: Bernardo
authors.initials: B
authors.lastname: Pons-Estel
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.forename: Enrique
authors.initials: E
authors.lastname: de Ramón
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.forename: Nadia
authors.initials: N
authors.lastname: Barizzone
authors.forename: Gian Domenico
authors.initials: GD
authors.lastname: Sebastiani
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Gary G
authors.initials: GG
authors.lastname: Gilkeson
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Il
authors.initials: I
authors.lastname: Kim
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
mesh_terms: D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D050533:Glomerular Basement Membrane / Q000276:immunology; D006801:Humans; D007610:Kallikreins / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
chemical_list: D004247:DNA; D007610:Kallikreins