Stipendium Hungaricum Scholarship(Stipendium) Támogató: Tempus
Excessive renal TGF-β production and pro-fibrotic miRNAs are important drivers of
kidney fibrosis that lack any efficient treatment. Dysfunctional autophagy might play
an important role in the pathogenesis. We aimed to study the yet unknown effects of
peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone (Pio) on
renal autophagy and miRNA dysregulation during fibrosis. Mouse primary tubular epithelial
cells (PTEC) were isolated, pre-treated with 5 µM pioglitazone, and then stimulated
with 10 ng/mL TGF-β1 for 24 h. Male 10-week-old C57Bl6 control (CTL) and TGF-β overexpressing
mice were fed with regular chow (TGF) or Pio-containing chow (20 mg/kg/day) for 5
weeks (TGF + Pio). PTEC and kidneys were evaluated for mRNA and protein expression.
In PTEC, pioglitazone attenuated (p < 0.05) the TGF-β-induced up-regulation of Col1a1
(1.4-fold), Tgfb1 (2.2-fold), Ctgf (1.5-fold), Egr2 (2.5-fold) mRNAs, miR-130a (1.6-fold),
and miR-199a (1.5-fold), inhibited epithelial-to-mesenchymal transition, and rescued
autophagy function. In TGF mice, pioglitazone greatly improved kidney fibrosis and
related dysfunctional autophagy (increased LC3-II/I ratio and reduced SQSTM1 protein
content (p < 0.05)). These were accompanied by 5-fold, 3-fold, 12-fold, and 2-fold
suppression (p < 0.05) of renal Ccl2, Il6, C3, and Lgals3 mRNA expression, respectively.
Our results implicate that pioglitazone counteracts multiple pro-fibrotic processes
in the kidney, including autophagy dysfunction and miRNA dysregulation.
