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AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression

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 stu...

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Autores principales: Cook, H. Terence, Tarzi, Ruth, D'Souza, Zelpha, Laurent, Gaelle, Lin, Wei-Chou, Aitman, Timothy J., Mechta-Grigoriou, Fatima, Behmoaras, Jacques
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Investigative Pathology 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123878/
https://www.ncbi.nlm.nih.gov/pubmed/21640331
http://dx.doi.org/10.1016/j.ajpath.2011.03.006
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author Cook, H. Terence
Tarzi, Ruth
D'Souza, Zelpha
Laurent, Gaelle
Lin, Wei-Chou
Aitman, Timothy J.
Mechta-Grigoriou, Fatima
Behmoaras, Jacques
author_facet Cook, H. Terence
Tarzi, Ruth
D'Souza, Zelpha
Laurent, Gaelle
Lin, Wei-Chou
Aitman, Timothy J.
Mechta-Grigoriou, Fatima
Behmoaras, Jacques
author_sort Cook, H. Terence
collection PubMed
description 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.
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spelling pubmed-31238782011-12-28 AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression Cook, H. Terence Tarzi, Ruth D'Souza, Zelpha Laurent, Gaelle Lin, Wei-Chou Aitman, Timothy J. Mechta-Grigoriou, Fatima Behmoaras, Jacques Am J Pathol Regular Article 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. American Society for Investigative Pathology 2011-07 /pmc/articles/PMC3123878/ /pubmed/21640331 http://dx.doi.org/10.1016/j.ajpath.2011.03.006 Text en © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Regular Article
Cook, H. Terence
Tarzi, Ruth
D'Souza, Zelpha
Laurent, Gaelle
Lin, Wei-Chou
Aitman, Timothy J.
Mechta-Grigoriou, Fatima
Behmoaras, Jacques
AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression
title AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression
title_full AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression
title_fullStr AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression
title_full_unstemmed AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression
title_short AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression
title_sort ap-1 transcription factor jund confers protection from accelerated nephrotoxic nephritis and control podocyte-specific vegfa expression
topic Regular Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123878/
https://www.ncbi.nlm.nih.gov/pubmed/21640331
http://dx.doi.org/10.1016/j.ajpath.2011.03.006
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