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NDT Advance Access originally published online on July 25, 2008
Nephrology Dialysis Transplantation 2008 23(10):3065-3066; doi:10.1093/ndt/gfn402
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Crescentic nephritis—is it in your genes?*

Peter G. Tipping

Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia

Peter Tipping, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia. Tel: +61395945547; Fax: +61395946495; E-mail: peter.tipping{at}med.monash.edu.au

Keywords: genetics; JunD; macrophage; Wistar–Kyoto; glomerulonephritis

Crescentic glomerulonephritis is frequently associated with a rapid clinical course and poor outcome, particularly if treatment is delayed. The severity of the renal injury and the suboptimal treatment modalities for this disease have provided considerable impetus to studies of the underlying immuno-pathogenic mechanisms. Well-documented variation in susceptibility to crescentic glomerulonephritis between inbred strains of rodents has strongly suggested the influence of genetic predisposing factors in animal models. In mice, susceptibility to crescentic disease in strains showing strong Th1 responses to nephritogenic antigens indicates that genetic factors may operate (in part) through regulation of adaptive T helper subset responses [1,2]. Recent elegant work by Professor Cook and others from Imperial College London has identified genetic factors controlling innate immune responses [3,4] and intrinsic renal cell biology [5] that contribute to the exquisite susceptibility of Wistar Kyoto (WKY) rats to development of crescentic glomerulonephritis.

The work of Behmoaras et al. published recently in Nature Genetics [4] demonstrates that a polymorphism in the promoter region of Jund, the gene for the AP-1 transcription factor JunD, accounts for a significant component of the susceptibility of WKY rats to crescentic glomerulonephritis. It expands previous work by this group that identified seven genetic susceptibility loci (named Crgn1–7) and characterized one major locus (Crgn1) that augments macrophage activation via copy number polymorphisms of an Fc{gamma} receptor gene-related sequence (Fcgr3-rs) [3]. They used an approach involving backcrossing of susceptible WKY rats with resistant Lewis rats and selective intercrossing of their F2 offspring (introgression) to evaluate quantitative trait loci (QTLs) for susceptibility to crescentic glomerulonephritis. This approach allowed them to characterize a polymorphism of Jund in the second major locus (Crgn2) and to demonstrate its strong association with crescentic renal injury and its role in regulation of macrophage activation.

JunD is one of several AP-1 transcription factor subunits that form active homo- or hetero-dimers that regulate expression of genes involved in a variety of biological responses including inflammation. JunD is widely expressed in many cell types including in renal epithelial cells [6] and mesangial cells [7]. It has been shown to regulate lymphocyte proliferation and promote Th2 differentiation [8], to inhibit fibroblast proliferation [9] and to halt development of glomerulosclerosis and interstitial fibrosis following renal mass reduction in mice [10]. The polymorphism in the Jund promoter identified in WKY rats results in higher expression of JunD in macrophages and in non-nephritic glomeruli and is associated with increased macrophage recruitment in nephritic glomeruli. The role of JunD in regulation of macrophage function is not well defined. Previous studies in mouse macrophages have shown that cytokines and LPS increase expression of other AP-1 transcription factors but not JunD [8]. In contrast, Behmoaras showed that LPS enhanced JunD expression in rat and human macrophages. Furthermore, inhibition of Jund using siRNA inhibited LPS-stimulated IL-10, TNF-{alpha} and IL-6 production by human macrophages and iNOS expression and Fc stimulated oxidative burst activity in rat macrophages.

Although Jund expression was dysregulated in macro- phages from WKY rats [4], dysregulation of Jund was not observed in mesangial cells. This is of interest as previous studies by the same group involving bone marrow and kidney transplantation between WKY and MHC haplotype compatible non-susceptible Lewis rats showed that part of the susceptibility to crescentic glomerulonephritis in WKY rats could be attributed to intrinsic renal cell factors [5]. Cultured mesangial cells from WKY kidneys showed increased basal and TNF-{alpha} and aggregated IgG-stimulated MCP-1 production. It is possible that one or more of the other six crescentic glomerulonephritis susceptibility loci (Crgn1, 3–7) identified in WKY rats [3] may be associated with these augmented mesangial cell inflammatory responses.

Crescentic glomerulonephritis in humans is frequently associated with evidence of autoimmunity, e.g. circulating anti-neutrophil cytoplasmic, anti-DNA or anti-GBM antibodies. Although these studies in WKY rats did not employ an autoimmune model of crescentic GN, other studies have started to define genetic susceptibility using autoimmune models. Susceptibility to autoimmune anti-GBM glomerulonephritis in WKY rats has been associated with inflammatory and renal factors independent of the MHC haplotype or the gene encoding the autoantigen ({alpha}3(IV)NC1) [11,12]. In SCG/Kj mice that develop spontaneous crescentic glomerulonephritis associated with myeloperoxidase-specific anti-neutrophil cytoplasmic antibodies, 14 quantitative trait loci independent of their Fas gene mutation have been mapped [13].

A significant achievement of the work by Behmoaras et al. [4] is their demonstration that an animal model can be used to define specific genetic defects in a complex inflammatory disease by working backwards from a clinically relevant phenotype to a mutated gene. The association of an increased incidence of human lupus nephritis with low copy number of FCGR3B (the human equivalent of copy number polymorphisms of Crgn-1 in WKY rats) [3] demonstrates the potential relevance of studies in inbred rats to human crescentic glomerulonephritis. The next step is to determine if genetic defects in Jund are associated with susceptibility to crescentic glomerulonephritis in humans and, if so, to explore how this knowledge may be used to aid prevention, diagnosis and treatment. It is possible that JunD may be a useful therapeutic target in crescentic glomerulonephritis or that Jund may be a relevant susceptibility gene in other more prevalent human inflammatory diseases (such as atherosclerosis) where macrophages are important mediators of injury.

Nephrologists are starting to appreciate that genetics may play an important role in determining susceptibility to crescentic glomerulonephritis in humans, particularly where autoimmunity is involved. Studies in animal models may provide significant novel insights into the specific genetic loci and the pathogenic mechanisms involved.

Conflict of interest statement. None declared.



   Notes
 
* Comment on: Behmoaras J, Bhangal G, Smith J et al. Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility. Nat Genet 2008; 40: 553–559. Published online: 28 April 2008| doi:10.1038/ng.137. Back



   References
Top
 References
 

  1. Holdsworth SR, Kitching AR, Tipping PG. Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis. Kidney Int (1999) 55:1198–1216.[CrossRef][Web of Science][Medline]
  2. Kalluri R, Danoff TM, Okada H, et al. Susceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice. J Clin Invest (1997) 100:2263–2275.[Web of Science][Medline]
  3. Aitman TJ, Dong R, Vyse TJ, et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature (2006) 439:851–855.[CrossRef][Web of Science][Medline]
  4. Behmoaras J, Bhangal G, Smith J, et al. Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility. Nat Genet (2008) 40:553–559.[CrossRef][Web of Science][Medline]
  5. Smith J, Lai PC, Behmoaras J, et al. Genes expressed by both mesangial cells and bone marrow-derived cells underlie genetic susceptibility to crescentic glomerulonephritis in the rat. J Am Soc Nephrol (2007) 18:1816–1823.[Abstract/Free Full Text]
  6. Hock TD, Liby K, Wright MM, et al. JunB and JunD regulate human heme oxygenase-1 gene expression in renal epithelial cells. J Biol Chem (2007) 282:6875–6886.[Abstract/Free Full Text]
  7. Weigert C, Sauer U, Brodbeck K, et al. AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-beta1 promoter in mesangial cells. J Am Soc Nephrol (2000) 11:2007–2016.[Abstract/Free Full Text]
  8. Tengku-Muhammad TS, Hughes TR, Foka P, et al. Cytokine-mediated differential regulation of macrophage activator protein-1 genes. Cytokine (2000) 12:720–726.[CrossRef][Web of Science][Medline]
  9. Jochum W, Passegue E, Wagner EF. AP-1 in mouse development and tumorigenesis. Oncogene (2001) 20:2401–2412.[CrossRef][Web of Science][Medline]
  10. Pillebout E, Weitzman JB, Burtin M, et al. JunD protects against chronic kidney disease by regulating paracrine mitogens. J Clin Invest (2003) 112:843–852.[CrossRef][Web of Science][Medline]
  11. Reynolds J, Albouainain A, Duda MA, et al. Strain susceptibility to active induction and passive transfer of experimental autoimmune glomerulonephritis in the rat. Nephrol Dial Transplant (2006) 21:3398–3408.[Abstract/Free Full Text]
  12. Reynolds J, Cook PR, Ryan JJ, et al. Segregation of experimental autoimmune glomerulonephritis as a complex genetic trait and exclusion of Col4a3 as a candidate gene. Exp Nephrol (2002) 10:402–407.[CrossRef][Web of Science][Medline]
  13. Hamano Y, Tsukamoto K, Abe M, et al. Genetic dissection of vasculitis, myeloperoxidase-specific antineutrophil cytoplasmic autoantibody production, and related traits in spontaneous crescentic glomerulonephritis-forming/Kinjoh mice. J Immunol (2006) 176:3662–3673.[Abstract/Free Full Text]
Received for publication: 13. 6.08
Accepted in revised form: 24. 6.08


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This Article
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