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Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function

Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and po...

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Autores principales: Chen, Tai-Di, Rotival, Maxime, Chiu, Ling-Yin, Bagnati, Marta, Ko, Jeong-Hun, Srivastava, Prashant K., Petretto, Enrico, Pusey, Charles D., Lai, Ping-Chin, Aitman, Timothy J., Cook, H. Terence, Behmoaras, Jacques
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Genetics Society of America 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499168/
https://www.ncbi.nlm.nih.gov/pubmed/28450461
http://dx.doi.org/10.1534/genetics.116.197376
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author Chen, Tai-Di
Rotival, Maxime
Chiu, Ling-Yin
Bagnati, Marta
Ko, Jeong-Hun
Srivastava, Prashant K.
Petretto, Enrico
Pusey, Charles D.
Lai, Ping-Chin
Aitman, Timothy J.
Cook, H. Terence
Behmoaras, Jacques
author_facet Chen, Tai-Di
Rotival, Maxime
Chiu, Ling-Yin
Bagnati, Marta
Ko, Jeong-Hun
Srivastava, Prashant K.
Petretto, Enrico
Pusey, Charles D.
Lai, Ping-Chin
Aitman, Timothy J.
Cook, H. Terence
Behmoaras, Jacques
author_sort Chen, Tai-Di
collection PubMed
description Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.
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spelling pubmed-54991682017-07-10 Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function Chen, Tai-Di Rotival, Maxime Chiu, Ling-Yin Bagnati, Marta Ko, Jeong-Hun Srivastava, Prashant K. Petretto, Enrico Pusey, Charles D. Lai, Ping-Chin Aitman, Timothy J. Cook, H. Terence Behmoaras, Jacques Genetics Investigations Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation. Genetics Society of America 2017-06 2017-04-24 /pmc/articles/PMC5499168/ /pubmed/28450461 http://dx.doi.org/10.1534/genetics.116.197376 Text en Copyright © 2017 Chen et al. Available freely online through the author-supported open access option. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Investigations
Chen, Tai-Di
Rotival, Maxime
Chiu, Ling-Yin
Bagnati, Marta
Ko, Jeong-Hun
Srivastava, Prashant K.
Petretto, Enrico
Pusey, Charles D.
Lai, Ping-Chin
Aitman, Timothy J.
Cook, H. Terence
Behmoaras, Jacques
Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function
title Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function
title_full Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function
title_fullStr Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function
title_full_unstemmed Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function
title_short Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function
title_sort identification of ceruloplasmin as a gene that affects susceptibility to glomerulonephritis through macrophage function
topic Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499168/
https://www.ncbi.nlm.nih.gov/pubmed/28450461
http://dx.doi.org/10.1534/genetics.116.197376
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