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

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)
187 Downloads (Pure)

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.

Original languageEnglish
Article numbere0157288
Number of pages23
JournalPLoS ONE
Volume11
Issue number7
DOIs
Publication statusPublished - 5 Jul 2016

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this