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Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria
Protein overload of proximal tubular cells (PTCs) can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated whether prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive inters...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043717/ https://www.ncbi.nlm.nih.gov/pubmed/29914975 http://dx.doi.org/10.1042/BSR20180762 |
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author | Faustino, Viviane Dias Arias, Simone Costa Alarcon Ferreira Ávila, Victor Foresto-Neto, Orestes Zambom, Fernanda Florencia Fregnan Machado, Flavia Gomes Machado dos Reis, Luciene Malheiros, Denise Maria Avancini Costa Volpini, Rildo Aparecido Camara, Niels Olsen Saraiva Zatz, Roberto Fujihara, Clarice Kazue |
author_facet | Faustino, Viviane Dias Arias, Simone Costa Alarcon Ferreira Ávila, Victor Foresto-Neto, Orestes Zambom, Fernanda Florencia Fregnan Machado, Flavia Gomes Machado dos Reis, Luciene Malheiros, Denise Maria Avancini Costa Volpini, Rildo Aparecido Camara, Niels Olsen Saraiva Zatz, Roberto Fujihara, Clarice Kazue |
author_sort | Faustino, Viviane Dias |
collection | PubMed |
description | Protein overload of proximal tubular cells (PTCs) can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated whether prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury, and whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin nephropathy (ADR). Adult male Munich–Wistar rats received a single dose of ADR (5 mg/kg, iv), being followed for 2, 4, or 20 weeks. Massive albuminuria was associated with early activation of both the NF-κB and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis, and renal functional loss were observed. Administration of mycophenolate mofetil (MMF), 10 mg/kg/day, prevented activation of both innate and adaptive immunity, as well as renal oxidative stress and renal fibrosis. Moreover, MMF treatment was associated with shifting of M from the M1 to the M2 phenotype. In cultivated NRK52-E cells, excess albumin increased the protein content of Toll-like receptor (TLR) 4 (TLR4), NLRP3, MCP-1, IL6, IL-1β, Caspase-1, α-actin, and collagen-1. Silencing of TLR4 and/or NLRP3 mRNA abrogated this proinflammatory/profibrotic behavior. Simultaneous activation of innate and adaptive immunity may be key to the development of renal injury in heavy proteinuric disease. Inhibition of specific components of innate and/or adaptive immunity may be the basis for future strategies to prevent chronic kidney disease (CKD) in this setting. |
format | Online Article Text |
id | pubmed-6043717 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60437172018-07-18 Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria Faustino, Viviane Dias Arias, Simone Costa Alarcon Ferreira Ávila, Victor Foresto-Neto, Orestes Zambom, Fernanda Florencia Fregnan Machado, Flavia Gomes Machado dos Reis, Luciene Malheiros, Denise Maria Avancini Costa Volpini, Rildo Aparecido Camara, Niels Olsen Saraiva Zatz, Roberto Fujihara, Clarice Kazue Biosci Rep Research Articles Protein overload of proximal tubular cells (PTCs) can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated whether prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury, and whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin nephropathy (ADR). Adult male Munich–Wistar rats received a single dose of ADR (5 mg/kg, iv), being followed for 2, 4, or 20 weeks. Massive albuminuria was associated with early activation of both the NF-κB and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis, and renal functional loss were observed. Administration of mycophenolate mofetil (MMF), 10 mg/kg/day, prevented activation of both innate and adaptive immunity, as well as renal oxidative stress and renal fibrosis. Moreover, MMF treatment was associated with shifting of M from the M1 to the M2 phenotype. In cultivated NRK52-E cells, excess albumin increased the protein content of Toll-like receptor (TLR) 4 (TLR4), NLRP3, MCP-1, IL6, IL-1β, Caspase-1, α-actin, and collagen-1. Silencing of TLR4 and/or NLRP3 mRNA abrogated this proinflammatory/profibrotic behavior. Simultaneous activation of innate and adaptive immunity may be key to the development of renal injury in heavy proteinuric disease. Inhibition of specific components of innate and/or adaptive immunity may be the basis for future strategies to prevent chronic kidney disease (CKD) in this setting. Portland Press Ltd. 2018-07-13 /pmc/articles/PMC6043717/ /pubmed/29914975 http://dx.doi.org/10.1042/BSR20180762 Text en © 2018 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Articles Faustino, Viviane Dias Arias, Simone Costa Alarcon Ferreira Ávila, Victor Foresto-Neto, Orestes Zambom, Fernanda Florencia Fregnan Machado, Flavia Gomes Machado dos Reis, Luciene Malheiros, Denise Maria Avancini Costa Volpini, Rildo Aparecido Camara, Niels Olsen Saraiva Zatz, Roberto Fujihara, Clarice Kazue Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria |
title | Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria |
title_full | Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria |
title_fullStr | Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria |
title_full_unstemmed | Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria |
title_short | Simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria |
title_sort | simultaneous activation of innate and adaptive immunity participates in the development of renal injury in a model of heavy proteinuria |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043717/ https://www.ncbi.nlm.nih.gov/pubmed/29914975 http://dx.doi.org/10.1042/BSR20180762 |
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