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Troglitazone attenuates TGF-β1-induced EMT in alveolar epithelial cells via a PPARγ-independent mechanism

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EHRHARDT, CARSTEN;

Subject Keywords: AKT signaling cascade; Immunology, Inflammation & Infection;
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Peroxisome proliferator activated receptor ? (PPAR?) agonists are effective antifibrotic agents in a number of tissues. Effects of these agents on epithelial-mesenchymal transition (EMT) of primary alveolar epithelial cells (AEC) and potential mechanisms underlying effects on EMT have not been well delineated. We examined effects of troglitazone, a synthetic PPAR? agonist, on transforming growth factor (TGF)-?1-induced EMT in primary rat AEC and an alveolar epithelial type II (AT2) cell line (RLE-6TN). TGF-?1 (2.5 ng/mL) induced EMT in both cell types, as evidenced by acquisition of spindle-like morphology, increased expression of the mesenchymal marker ?-smooth muscle actin (?-SMA) and downregulation of the tight junctional protein zonula occludens-1 (ZO-1). Concurrent treatment with troglitazone (or rosiglitazone), ameliorated effects of TGF-?1. Furthermore, following stimulation with TGF-?1 for 6 days, troglitazone reversed EMT-related morphological changes and restored both epithelial and mesenchymal markers to control levels. Treatment with GW9662 (an irreversible PPAR? antagonist), or overexpression of a PPAR? dominant negative construct, failed to inhibit these effects of troglitazone in AEC. Troglitazone not only attenuated TGF-?1-induced phosphorylation of Akt and glycogen synthase kinase (GSK)-3?, but also inhibited nuclear translocation of ?-catenin, phosphorylation of Smad2 and Smad3 and upregulation of the EMT-associated transcription factor SNAI1. These results demonstrate inhibitory actions of troglitazone on TGF-?1-induced EMT in AEC via a PPAR?-independent mechanism likely through inhibition of ?-catenin-dependent signaling downstream of TGF-?1, supporting a role for interactions between TGF-? and Wnt/?-catenin signaling pathways in EMT.

Suggested citation:

EHRHARDT, CARSTEN; . () Troglitazone attenuates TGF-β1-induced EMT in alveolar epithelial cells via a PPARγ-independent mechanism [Online]. Available from: http://publichealthwell.ie/node/823407 [Accessed: 17th September 2019].

  

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