Transforming Growth Factor beta 1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis
- Authors
- Das, Ranjan; Xu, Shanhua; Tuyet Thi Nguyen; Quan, Xianglan; Choi, Seong-Kyung; Kim, Soo-Jin; Lee, Eun Young; Cha, Seung-Kuy; Park, Kyu-Sang
- Issue Date
- 25-Dec-2015
- Publisher
- American Society for Biochemistry and Molecular Biology Inc.
- Keywords
- ERK; NADPH oxidase; SMAD transcription factor; TGF-β; apoptosis; mammalian target of rapamycin (mTOR); podocyte; reactive oxygen species (ROS)
- Citation
- Journal of Biological Chemistry, v.290, no.52, pp 30830 - 30842
- Pages
- 13
- Journal Title
- Journal of Biological Chemistry
- Volume
- 290
- Number
- 52
- Start Page
- 30830
- End Page
- 30842
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/9960
- DOI
- 10.1074/jbc.M115.703116
- ISSN
- 0021-9258
1083-351X
- Abstract
- TGF-beta is a pleiotropic cytokine that accumulates during kidney injuries, resulting in various renal diseases. We have reported previously that TGF-beta 1 induces the selective up-regulation of mitochondrial Nox4, playing critical roles in podocyte apoptosis. Here we investigated the regulatory mechanism of Nox4 up-regulation by mTORC1 activation on TGF-beta 1-induced apoptosis in immortalized podocytes. TGF-beta 1 treatment markedly increased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4EBP1. Blocking TGF-beta receptor I with SB431542 completely blunted the phosphorylation of mTOR, p70S6K, and 4EBP1. Transient adenoviral overexpression of mTOR-WT and constitutively active mTOR Delta augmented TGF-beta 1-treated Nox4 expression, reactive oxygen species (ROS) generation, and apoptosis, whereas mTOR kinase-dead suppressed the above changes. In addition, knockdown of mTOR mimicked the effect of mTOR-KD. Inhibition ofmTORC1by low-dose rapamycin or knockdown of p70S6K protected podocytes through attenuation of Nox4 expression and subsequent oxidative stress-induced apoptosis by TGF-beta 1. Pharmacological inhibition of the MEK-ERK cascade, but not the PI3K-Akt-TSC2 pathway, abolished TGF-beta 1-induced mTOR activation. Inhibition of either ERK1/2 or mTORC1 did not reduce the TGF-beta 1-stimulated increase in Nox4 mRNA level but significantly inhibited total Nox4 expression, ROS generation, and apoptosis induced by TGF-beta 1. Moreover, double knockdown of Smad2 and 3 or only Smad4 completely suppressed TGF-beta 1-induced ERK1/2-mTOR activation. Our data suggest that TGF-beta 1 increases translation of Nox4 through the Smad-ERK1/2-mTORC1 axis, which is independent of transcriptional regulation. Activation of this pathway plays a crucial role in ROS generation and mitochondrial dysfunction, leading to podocyte apoptosis. Therefore, inhibition of the ERK1/2-mTORC1 pathway could be a potential therapeutic and preventive target in proteinuric and chronic kidney diseases.
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Collections - College of Medicine > Department of Internal Medicine > 1. Journal Articles
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