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.

[1]  Chandra Mohan,et al.  Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. , 2005, The Journal of clinical investigation.

[2]  H. Margolius,et al.  Urinary Kallikrein Excretion in Hypertensive Man: Relationships to Sodium intake and Sodium‐Retaining Steroids , 1974, Circulation research.

[3]  K. Bhoola,et al.  Bioregulation of kinins: kallikreins, kininogens, and kininases. , 1992, Pharmacological reviews.

[4]  C. Mohan,et al.  Strain distribution pattern of immune nephritis--a follow-up study. , 2008, International immunology.

[5]  C. Mohan,et al.  Enhanced susceptibility to end-organ disease in the lupus-facilitating NZW mouse strain. , 2003, Arthritis and rheumatism.

[6]  O. Carretero,et al.  The renal kallikrein-kinin system. , 1980, The American journal of physiology.

[7]  Geoffrey Hom,et al.  Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. , 2008, The New England journal of medicine.

[8]  R. Richards,et al.  Mouse glandular kallikrein genes. Structure and partial sequence analysis of the kallikrein gene locus. , 1987, The Journal of biological chemistry.

[9]  J. Harley,et al.  Localization and replication of the systemic lupus erythematosus linkage signal at 4p16: interaction with 2p11, 12q24 and 19q13 in European Americans , 2006, Human Genetics.

[10]  G. Gilkeson,et al.  Nephritogenic autoantibodies in lupus: current concepts and continuing controversies. , 1996, Arthritis and rheumatism.

[11]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[12]  X. Xu,et al.  Role of endothelial kinins in control of coronary nitric oxide production. , 1997, Hypertension.

[13]  E. Wakeland,et al.  Genetic dissection of systemic lupus erythematosus. , 1999, Current opinion in immunology.

[14]  L. Chao,et al.  The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction , 2006, Biological chemistry.

[15]  B. Croker,et al.  Functional dissection of systemic lupus erythematosus using congenic mouse strains. , 1997, Journal of immunology.

[16]  D. Pisetsky.  Anti-DNA and autoantibodies. , 2000, Current Opinion in Rheumatology.

[17]  L. Orozco,et al.  Genetic association of IRF5 with SLE in Mexicans: higher frequency of the risk haplotype and its homozygozity than Europeans , 2007, Human Genetics.

[18]  C. Mohan,et al.  Experimental anti-GBM disease as a tool for studying spontaneous lupus nephritis. , 2007, Clinical immunology.

[19]  G. Yousef,et al.  Genomic organization of the human kallikrein gene family on chromosome 19q13.3-q13.4. , 2000, Biochemical and biophysical research communications.

[20]  L. Chao,et al.  Reversal of renal fibrosis, inflammation, and glomerular hypertrophy by kallikrein gene delivery. , 2006, Human gene therapy.

[21]  D. Cox,et al.  Structure of mouse kallikrein gene family suggests a role in specific processing of biologically active peptides , 1983, Nature.

[22]  S. Hunt,et al.  Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. , 2002, Journal of the American Society of Nephrology : JASN.

[23]  L. Chao,et al.  Adenovirus-mediated kallikrein gene delivery reverses salt-induced renal injury in Dahl salt-sensitive rats. , 1998, Kidney international.

[24]  C. Mohan,et al.  Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. , 1999, Journal of immunology.

[25]  H. Hsieh,et al.  Bradykinin‐induced p42/p44 MAPK phosphorylation and cell proliferation via Src, EGF receptors, and PI3‐K/Akt in vascular smooth muscle cells , 2005, Journal of cellular physiology.

[26]  L. Chao,et al.  Human kallikrein gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in Dahl salt-sensitive rats. , 1998, Human gene therapy.

[27]  L. Chao,et al.  Kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibition of inflammation and apoptosis. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[28]  V. Kelley,et al.  Lupus nephritis: update on pathogenesis and disease mechanisms. , 1999, Seminars in nephrology.

[29]  B. Hahn.  Antibodies to DNA. , 1998, The New England journal of medicine.

[30]  A. Satterthwaite,et al.  Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication , 2006, Science.

[31]  L. Chao,et al.  Tissue kallikrein attenuates salt-induced renal fibrosis by inhibition of oxidative stress. , 2004, Kidney international.

[32]  J. Terwilliger,et al.  A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. , 2000, Journal of autoimmunity.

[33]  F. Marceau,et al.  Pharmacology of kinins: their relevance to tissue injury and inflammation. , 1983, General pharmacology.

[34]  Quanzhen Li,et al.  A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[35]  B. Rosner,et al.  Stability of Blood Pressure Rank and Urinary Kallikrein Concentration in Childhood: An Eight-Year Follow-Up , 1978, Circulation.

[36]  A. Davidson,et al.  An in vitro assay for detection of glomerular binding IgG autoantibodies in patients with systemic lupus erythematosus. , 1996, The Journal of clinical investigation.

[37]  C. Mohan,et al.  Sle3 and Sle5 can independently couple with Sle1 to mediate severe lupus nephritis , 2007, Genes and Immunity.

[38]  O. Pankewycz,et al.  Polyreactive autoantibodies are nephritogenic in murine lupus nephritis. , 1987, Journal of immunology.

[39]  R. Cantor,et al.  Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus , 2006, Genes and Immunity.

[40]  Javier Martín,et al.  Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus. , 2007, Arthritis and rheumatism.

[41]  J. Schanstra,et al.  In vivo bradykinin B2 receptor activation reduces renal fibrosis. , 2002, The Journal of clinical investigation.

[42]  D. Boumpas,et al.  High-risk features of lupus nephritis: importance of race and clinical and histological factors in 166 patients. , 1995, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[43]  E. Wakeland,et al.  Polygenic control of susceptibility to murine systemic lupus erythematosus. , 1994, Immunity.

[44]  M. Walport,et al.  Open access, freely available online PLoS BIOLOGY Spontaneous Autoimmunity in 129 and C57BL/6 Mice—Implications for Autoimmunity Described in Gene-Targeted Mice , 2022 .

[45]  Chandra Mohan,et al.  Strain Distribution Pattern of Susceptibility to Immune-Mediated Nephritis1 , 2004, The Journal of Immunology.

[46]  Marta E Alarcón-Riquelme,et al.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci , 2008, Nature Genetics.

[47]  C. Mohan,et al.  T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells. , 2005, The Journal of clinical investigation.

[48]  C. Mohan,et al.  Regulation of B Cell Tolerance by the Lupus Susceptibility Gene Ly108 , 2006, Science.

[49]  B. Croker,et al.  Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies. , 1999, The Journal of clinical investigation.

[50]  L. Chao,et al.  Kinin Infusion Prevents Renal Inflammation, Apoptosis, and Fibrosis via Inhibition of Oxidative Stress and Mitogen-Activated Protein Kinase Activity , 2007, Hypertension.

[51]  J F Fries,et al.  The 1982 revised criteria for the classification of systemic lupus erythematosus. , 1982, Arthritis and rheumatism.

[52]  L. Chao,et al.  Kallikrein–kinin in stroke, cardiovascular and renal disease , 2005, Experimental physiology.

[53]  H. Shin,et al.  Replication of the genetic effects of IFN regulatory factor 5 (IRF5) on systemic lupus erythematosus in a Korean population , 2007, Arthritis research & therapy.

[54]  D. Kono,et al.  Genetics of Systemic Autoimmunity in Mouse Models of Lupus , 2000, International reviews of immunology.

[55]  S. Rich,et al.  Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans. , 1997, Kidney international.

[56]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[57]  M. Petri,et al.  Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[58]  O. Smithies,et al.  Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[59]  S. Rich,et al.  Association of the tissue kallikrein gene promoter with ESRD and hypertension. , 2002, Kidney international.