title: AP-1 transcription factor JunD confers protection from accelerated nephrotoxic nephritis and control podocyte-specific Vegfa expression.
abstract: Genetic investigation of crescentic glomerulonephritis (Crgn) susceptibility in the Wistar Kyoto rat, a strain uniquely susceptible to nephrotoxic nephritis (NTN), allowed us to positionally clone the activator protein-1 transcription factor Jund as a susceptibility gene associated with Crgn. To study the influence of Jund deficiency (Jund(-/-)) on immune-mediated renal disease, susceptibility to accelerated NTN was examined in Jund(-/-) mice and C57BL/6 wild-type (WT) controls. Jund(-/-) mice showed exacerbated glomerular crescent formation and macrophage infiltration, 10 days after NTN induction. Serum urea levels were also significantly increased in the Jund(-/-) mice compared with the WT controls. There was no evidence of immune response differences between Jund(-/-) and WT animals because the quantitative immunofluorescence for sheep and mouse IgG deposition in glomeruli was similar. Because murine Jund was inactivated by replacement with a bacterial LacZ reporter gene, we then investigated its glomerular expression by IHC and found that the Jund promoter is mainly active in Jund(-/-) podocytes. Furthermore, cultured glomeruli from Jund(-/-) mice showed relatively increased expression of vascular endothelial growth factor A (Vegfa), Cxcr4, and Cxcl12, well-known HIF target genes. Accordingly, small-interfering RNA-mediated JUND knockdown in conditionally immortalized human podocyte cell lines led to increased VEGFA and HIF1A expression. Our findings suggest that deficiency of Jund may cause increased oxidative stress in podocytes, leading to altered VEGFA expression and subsequent glomerular injury in Crgn.
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Ruth
authors.initials: R
authors.lastname: Tarzi
authors.forename: Zelpha
authors.initials: Z
authors.lastname: D'Souza
authors.forename: Gaelle
authors.initials: G
authors.lastname: Laurent
authors.forename: Wei-Chou
authors.initials: WC
authors.lastname: Lin
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.forename: Fatima
authors.initials: F
authors.lastname: Mechta-Grigoriou
authors.forename: Jacques
authors.initials: J
authors.lastname: Behmoaras
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007074:Immunoglobulin G; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A