Back to Search
Start Over
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.
- Source :
-
PloS one [PLoS One] 2016 Jul 05; Vol. 11 (7), pp. e0157288. Date of Electronic Publication: 2016 Jul 05 (Print Publication: 2016). - Publication Year :
- 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.<br />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.<br />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.<br />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.<br />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.
- Subjects :
- Acute Kidney Injury chemically induced
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
Models, Biological
Myofibroblasts drug effects
Myofibroblasts metabolism
Pericytes drug effects
Rats, Wistar
Signal Transduction drug effects
Smad Proteins metabolism
Time Factors
Transforming Growth Factor beta immunology
Acute Kidney Injury metabolism
Mitochondrial Proteins metabolism
Pericytes metabolism
Receptor, Platelet-Derived Growth Factor beta metabolism
Transforming Growth Factor beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 27379382
- Full Text :
- https://doi.org/10.1371/journal.pone.0157288