Tgf-β1 induces autophagy and promotes apoptosis in renal tubular epithelial cells
Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that regulates cell growth, differentiation, apoptosis and autophagy in various cell types. It has been shown that TGF-β1-driven autophagy represents a novel mechanism of tubular decomposition, leading to renal interstitial fibrosi...
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Published in | International journal of molecular medicine Vol. 29; no. 5; pp. 781 - 790 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
D.A. Spandidos
01.05.2012
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Online Access | Get full text |
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Summary: | Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that
regulates cell growth, differentiation, apoptosis and autophagy in various cell
types. It has been shown that TGF-β1-driven autophagy represents a novel mechanism
of tubular decomposition, leading to renal interstitial fibrosis. However, the
exact mechanism by which TGF-β1 regulates autophagy is still poorly understood.
In the present study, we investigated the effects of exogenous TGF-β1 on cultured
human renal proximal tubular epithelial cells (HRPTEpiCs). Presence of TGF-β1
in the medium induced accumulation of autophagosomes in a time- and dose-dependent
manner as seen by monitoring the marker LC3 by confocal fluorescence microscopy
and immunoblotting. In addition, TGF-β1 induced upregulation of autophagy-related
genes, Atg5, Atg7 and Beclin1. Importantly, increased generation of reactive oxygen
species (ROS) and enhanced expression of NADPH oxidases were found to be associated
with the TGF-β1-induced autophagy. Conversely, treatment with inhibitors of NADPH
oxidase markedly reversed the autophagic effects of TGF-β1. Apoptotic effects
were evaluated by the TUNEL assay, measuring mitochondrial membrane potential
and monitoring expression of the pro- and anti-apoptotic genes, Bim and Bcl-2,
respectively. Transcriptional silencing of the above three autophagy-related genes
in HRPTEpiCs caused attenuation of TGF-β1-mediated apoptosis. Similarly, when
autophagy was prevented at an early stage by application of 3-methyladenine, the
pro-apoptotic effects of TGF-β1 were attenuated. These observations suggest that
in HRPTEpiCs TGF-β1 promotes autophagy through the generation of ROS, which contributes
to its proapoptotic effect. |
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ISSN: | 1107-3756 1791-244X |
DOI: | 10.3892/ijmm.2012.911 |