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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Laboratory of Experimental Nephrology, Department of Biochemistry, Faculty of Medicine, ULB, Brussels, Belgium.|Nephrology Department, Erasme Hospital, ULB, Brussels, Belgium.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Pozdzik
authors.affiliation: Laboratory of General Physiology, URPHYM, University of Namur, Namur, Belgium.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Giordano
authors.affiliation: CardioMetabolic and Renal Research, Cell Biology, Genzyme Corporation, Framingham, Massachusetts, United States of America.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Laboratory of Experimental Nephrology, Department of Biochemistry, Faculty of Medicine, ULB, Brussels, Belgium.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.affiliation: Pathology and Electron Microscopy, CHU La Miletrie, Poitiers, France.|INSERM U 1082, Poitiers, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Quellard
authors.affiliation: Pathology and Electron Microscopy, CHU La Miletrie, Poitiers, France.|INSERM U 1082, Poitiers, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Godet
authors.affiliation: Laboratory of Experimental Nephrology, Department of Biochemistry, Faculty of Medicine, ULB, Brussels, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: De Prez
authors.affiliation: Laboratory of Experimental Nephrology, Department of Biochemistry, Faculty of Medicine, ULB, Brussels, Belgium.
authors.forename: Cécile
authors.initials: C
authors.lastname: Husson
authors.affiliation: Laboratory of General Physiology, URPHYM, University of Namur, Namur, Belgium.
authors.forename: Anne-Emilie
authors.initials: AE
authors.lastname: Declèves
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, London, United Kingdom.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Pathology and Electron Microscopy, CHU La Miletrie, Poitiers, France.|INSERM U 1082, Poitiers, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Goujon
authors.affiliation: Pathology Department, Tenon Hospital, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Brochériou-Spelle
authors.affiliation: CardioMetabolic and Renal Research, Cell Biology, Genzyme Corporation, Framingham, Massachusetts, United States of America.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.affiliation: Laboratory of General Physiology, URPHYM, University of Namur, Namur, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Caron
authors.affiliation: Laboratory of Experimental Nephrology, Department of Biochemistry, Faculty of Medicine, ULB, Brussels, Belgium.|Nephrology Department, Erasme Hospital, ULB, Brussels, Belgium.
authors.forename: Joëlle L
authors.initials: JL
authors.lastname: Nortier
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D034341:Aristolochic Acids; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism*; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D034341:Aristolochic Acids; D024101:Mitochondrial Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D020797:Receptor, Platelet-Derived Growth Factor beta