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

Agnieszka A. Pozdzik, Laetitia Giordano, Gang Li, Marie Hélène Antoine, Nathalie Quellard, Julie Godet, Eric De Prez, Cécile Husson, Anne Emilie Declèves, Volker M. Arlt, Jean Michel Goujon, Isabelle Brochériou-Spelle, Steven R. Ledbetter, Nathalie Caron, Joëlle L. Nortier

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

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.

langueAnglais
Numéro d'articlee0157288
journalPLoS ONE
Volume11
Numéro7
Les DOIs
étatPublié - 1 juil. 2016

Empreinte digitale

Platelet-Derived Growth Factor beta Receptor
Pericytes
transforming growth factor beta
Acute Kidney Injury
Transforming Growth Factor beta
edema
preserves
Wistar Rats
Rats
Edema
Myofibroblasts
Chemical activation
kidneys
renal function
kidney diseases
Kidney
Endoplasmic Reticulum
endoplasmic reticulum
acids
rats

Citer ceci

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. Dans: PLoS ONE. 2016 ; Vol 11, Numéro 7.
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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",
abstract = "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.",
author = "Pozdzik, {Agnieszka A.} and Laetitia Giordano and Gang Li and Antoine, {Marie H{\'e}l{\`e}ne} and Nathalie Quellard and Julie Godet and {De Prez}, Eric and C{\'e}cile Husson and Decl{\`e}ves, {Anne Emilie} and Arlt, {Volker M.} and Goujon, {Jean Michel} and Isabelle Broch{\'e}riou-Spelle and Ledbetter, {Steven R.} and Nathalie Caron and Nortier, {Jo{\"e}lle L.}",
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Pozdzik, AA, Giordano, L, Li, G, Antoine, MH, Quellard, N, Godet, J, De Prez, E, Husson, C, Declèves, AE, Arlt, VM, Goujon, JM, Brochériou-Spelle, I, Ledbetter, SR, Caron, N & Nortier, JL 2016, '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' PLoS ONE, VOL. 11, Numéro 7, e0157288. DOI: 10.1371/journal.pone.0157288

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.

Dans: PLoS ONE, Vol 11, Numéro 7, e0157288, 01.07.2016.

Résultats de recherche: Contribution à un journal/une revueArticle

TY - JOUR

T1 - 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

AU - Pozdzik,Agnieszka A.

AU - Giordano,Laetitia

AU - Li,Gang

AU - Antoine,Marie Hélène

AU - Quellard,Nathalie

AU - Godet,Julie

AU - De Prez,Eric

AU - Husson,Cécile

AU - Declèves,Anne Emilie

AU - Arlt,Volker M.

AU - Goujon,Jean Michel

AU - Brochériou-Spelle,Isabelle

AU - Ledbetter,Steven R.

AU - Caron,Nathalie

AU - Nortier,Joëlle L.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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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U2 - 10.1371/journal.pone.0157288

DO - 10.1371/journal.pone.0157288

M3 - Article

VL - 11

JO - PloS one

T2 - PloS one

JF - PloS one

SN - 1932-6203

IS - 7

M1 - e0157288

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