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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2018
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.
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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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