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Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats
BACKGROUND: The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target. AIMS: In this regard, we first confirmed the presence...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933370/ https://www.ncbi.nlm.nih.gov/pubmed/27379382 http://dx.doi.org/10.1371/journal.pone.0157288 |
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author | Pozdzik, Agnieszka A. Giordano, Laetitia Li, Gang Antoine, Marie-Hélène Quellard, Nathalie Godet, Julie De Prez, Eric Husson, Cécile Declèves, Anne-Emilie Arlt, Volker M. Goujon, Jean-Michel Brochériou-Spelle, Isabelle Ledbetter, Steven R. Caron, Nathalie Nortier, Joëlle L. |
author_facet | Pozdzik, Agnieszka A. Giordano, Laetitia Li, Gang Antoine, Marie-Hélène Quellard, Nathalie Godet, Julie De Prez, Eric Husson, Cécile Declèves, Anne-Emilie Arlt, Volker M. Goujon, Jean-Michel Brochériou-Spelle, Isabelle Ledbetter, Steven R. Caron, Nathalie Nortier, Joëlle L. |
author_sort | Pozdzik, Agnieszka A. |
collection | PubMed |
description | BACKGROUND: The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target. AIMS: In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN. MATERIALS AND METHODS: Neutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily. RESULTS: At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro. CONCLUSIONS: The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation. |
format | Online Article Text |
id | pubmed-4933370 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49333702016-07-18 Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats Pozdzik, Agnieszka A. Giordano, Laetitia Li, Gang Antoine, Marie-Hélène Quellard, Nathalie Godet, Julie De Prez, Eric Husson, Cécile Declèves, Anne-Emilie Arlt, Volker M. Goujon, Jean-Michel Brochériou-Spelle, Isabelle Ledbetter, Steven R. Caron, Nathalie Nortier, Joëlle L. PLoS One Research Article BACKGROUND: The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target. AIMS: In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN. MATERIALS AND METHODS: Neutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily. RESULTS: At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro. CONCLUSIONS: The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation. Public Library of Science 2016-07-05 /pmc/articles/PMC4933370/ /pubmed/27379382 http://dx.doi.org/10.1371/journal.pone.0157288 Text en © 2016 Pozdzik et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Pozdzik, Agnieszka A. Giordano, Laetitia Li, Gang Antoine, Marie-Hélène Quellard, Nathalie Godet, Julie De Prez, Eric Husson, Cécile Declèves, Anne-Emilie Arlt, Volker M. Goujon, Jean-Michel Brochériou-Spelle, Isabelle Ledbetter, Steven R. Caron, Nathalie Nortier, Joëlle L. Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats |
title | Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats |
title_full | Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats |
title_fullStr | Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats |
title_full_unstemmed | Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats |
title_short | Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats |
title_sort | blocking tgf-β signaling pathway preserves mitochondrial proteostasis and reduces early activation of pdgfrβ+ pericytes in aristolochic acid induced acute kidney injury in wistar male rats |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933370/ https://www.ncbi.nlm.nih.gov/pubmed/27379382 http://dx.doi.org/10.1371/journal.pone.0157288 |
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