Transforming Growth Factor ß1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis.
J Biol Chem
; 290(52): 30830-42, 2015 Dec 25.
Article
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| MEDLINE
| ID: mdl-26565025
ABSTRACT
TGF-ß is a pleiotropic cytokine that accumulates during kidney injuries, resulting in various renal diseases. We have reported previously that TGF-ß1 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-ß1-induced apoptosis in immortalized podocytes. TGF-ß1 treatment markedly increased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4EBP1. Blocking TGF-ß receptor I with SB431542 completely blunted the phosphorylation of mTOR, p70S6K, and 4EBP1. Transient adenoviral overexpression of mTOR-WT and constitutively active mTORΔ augmented TGF-ß1-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 of mTORC1 by low-dose rapamycin or knockdown of p70S6K protected podocytes through attenuation of Nox4 expression and subsequent oxidative stress-induced apoptosis by TGF-ß1. Pharmacological inhibition of the MEK-ERK cascade, but not the PI3K-Akt-TSC2 pathway, abolished TGF-ß1-induced mTOR activation. Inhibition of either ERK1/2 or mTORC1 did not reduce the TGF-ß1-stimulated increase in Nox4 mRNA level but significantly inhibited total Nox4 expression, ROS generation, and apoptosis induced by TGF-ß1. Moreover, double knockdown of Smad2 and 3 or only Smad4 completely suppressed TGF-ß1-induced ERK1/2-mTORactivation. Our data suggest that TGF-ß1 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Apoptosis
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NADPH Oxidasas
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Proteína Quinasa 1 Activada por Mitógenos
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Proteína Quinasa 3 Activada por Mitógenos
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Podocitos
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Factor de Crecimiento Transformador beta1
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Serina-Treonina Quinasas TOR
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2015
Tipo del documento:
Article