Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans.
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.
Liu
Kui
K
Department of Immunology and Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8884, USA.
Li
Quan-Zhen
QZ
Delgado-Vega
Angelica M
AM
Abelson
Anna-Karin
AK
Sánchez
Elena
E
Kelly
Jennifer A
JA
Li
Li
L
Liu
Yang
Y
Zhou
Jinchun
J
Yan
Mei
M
Ye
Qiu
Q
Liu
Shenxi
S
Xie
Chun
C
Zhou
Xin J
XJ
Chung
Sharon A
SA
Pons-Estel
Bernardo
B
Witte
Torsten
T
de Ramón
Enrique
E
Bae
Sang-Cheol
SC
Barizzone
Nadia
N
Sebastiani
Gian Domenico
GD
Merrill
Joan T
JT
Gregersen
Peter K
PK
Gilkeson
Gary G
GG
Kimberly
Robert P
RP
Vyse
Timothy J
TJ
Kim
Il
I
D'Alfonso
Sandra
S
Martin
Javier
J
Harley
John B
JB
Criswell
Lindsey A
LA
Wakeland
Edward K
EK
Alarcón-Riquelme
Marta E
ME
Mohan
Chandra
C
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
D004247:DNA; D007610:Kallikreins