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. 2016 Jul 5;11(7):e0157288. doi: 10.1371/journal.pone.0157288. eCollection 2016.

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.

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / prevention & control
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology
  • Aristolochic Acids
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Homeostasis / drug effects
  • Humans
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Mitochondrial Proteins / metabolism*
  • Models, Biological
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Pericytes / drug effects
  • Pericytes / metabolism*
  • Rats, Wistar
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • Time Factors
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*

Substances

  • Antibodies, Neutralizing
  • Aristolochic Acids
  • Mitochondrial Proteins
  • Smad Proteins
  • Transforming Growth Factor beta
  • Receptor, Platelet-Derived Growth Factor beta