Generation of endoplasmic reticulum stress-dependent reactive oxygen species mediates TGF-β1-induced podocyte migration. (22nd November 2021)

• Record Type: Journal Article
• Authors: Chen, Chien-An; Chang, Jer-Ming; Chen, Hung-Chun; Chang, Eddy-Essen
• Is Part Of: Journal of biochemistry. Volume 171:Number 3(2022)
• Page Start: 305
• Page End: 314
• Publication Date: 2021-11-22
• Subjects: eIF2α -- ER stress -- migration -- podocyte -- ROS -- TGF-β1; Biochemistry -- Periodicals; Biochemistry -- Periodicals; Electronic journals; 572.05
• DOI: 10.1093/jb/mvab128
• Languages: English
• ISSNs: 0021-924X

Abstract

Abstract: Podocyte migration results in proteinuria and glomerulonephropathy. Transforming growth factor-β1 (TGF-β1), 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-eIF2α or CHOP), intracellular ROS generation, integrin-β3 and cell adhesion and migration were studied in a treatment of experiment using TGF-β1 with and without the ER stress inhibitors: 4-phenylbutyric acid (4-PBA, a chemical chaperone), salubrinal (an eIF2α dephosphorylation inhibitor) and N-acetylcysteine (NAC, an antioxidant). ER stress biomarkers (p-eIF2α/eIF2α and GRP78), ROS generation and intergrin-β3 expression increased after TGF-β1 treatment. NAC down-regulated the expression of GRP78 after TGF-β1 treatment. 4-PBA attenuated TGF-β1-induced p-eIF2α/eIF2α, CHOP, ROS generation and intergrin-β3 expression. However, salubrinal did not inhibit TGF-β1-induced p-eIF2α/eIF2α, CHOP, ROS generation or integrin-β3 expression. NAC abrogated TGF-β1-induced integrin-β3 expression. At 24 h after treatment with TGF-β1, podocyte adhesion and migration increased. Furthermore, NAC, 4-PBA and an anti-interin-β3 antibody attenuated TGF-β1-induced podocyte adhesion and migration. This study demonstrated that TGF-β1-induced ER stress potentiates the generation of intracellular ROS to a high degree through the PERK/eIF2α/CHOP pathway. This intracellular ROS then mediates integrin-β3 expression, which regulates podocyte migration. Graphical Abstract: