4.2 Article

Generation of endoplasmic reticulum stress-dependent reactive oxygen species mediates TGF-beta 1-induced podocyte migration

期刊

JOURNAL OF BIOCHEMISTRY
卷 171, 期 3, 页码 305-314

出版社

OXFORD UNIV PRESS
DOI: 10.1093/jb/mvab128

关键词

eIF2 alpha; ER stress; migration; podocyte; ROS; TGF-beta 1

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Podocyte migration, a key factor in the development of proteinuria and glomerulonephropathy, is influenced by the interaction between Transforming growth factor-beta 1 (TGF beta 1), endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS). This study reveals that TGF-beta 1-induced ER stress leads to the generation of intracellular ROS and subsequent expression of integrin-beta 3, ultimately promoting podocyte migration.
Podocyte migration results in proteinuria and glomerulonephropathy. Transforming growth factor-beta 1 (TGF beta 1), endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) can mediate podocyte migration; however, the crosstalk between them is unclear. This study determined the relationships between these factors. ER stress biomarkers (GRP78, p-eIF2a or CHOP), intracellular ROS generation, integrin-beta 3 and cell adhesion andmigration were studied in a treatment of experiment using TGF-beta 1 with and without the ER stress inhibitors: 4-phenylbutyric acid (4-PBA, a chemical chaperone), salubrinal (an eIF2 alpha dephosphorylation inhibitor) and N-acetylcysteine (NAC, an antioxidant). ER stress biomarkers (p-eIF2 alpha/eIF2 alpha and GRP78), ROS generation and intergrin-beta 3 expression increased after TGF-beta 1 treatment. NAC downregulated the expression of GRP78 after TGF-beta 1 treatment. 4-PBA attenuated TGF-beta 1-induced p-eIF2 alpha/eIF2 alpha, CHOP, ROS generation and intergrin-beta 3 expression. However, salubrinal did not inhibit TGF beta 1-induced p-eIF2 alpha/eIF2 alpha, CHOP, ROS g or integrin-beta 3 expression. NAC abrogated TGF-beta 1-induced integrin-beta 3 expression. At 24 h after treatment with TGF-beta 1, podocyte adhesion and migration increased. Furthermore, NAC, 4-PBA and an anti-interin-beta 3 antibody attenuated TGF-beta 1-induced podocyte adhesion and migration. This study demonstrated that TGF-beta 1-induced ER stress potentiates the generation of intracellular ROS to a high degree through the PERK/eIF2 alpha/CHOP pathway. This intracellular ROS then mediates integrin-beta 3 expression, which regulates podocyte migration.eneration

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