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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
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.
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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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