Activation of Akt-dependent Nrf2/ARE pathway by restoration of Brg-1 remits high glucose-induced oxidative stress and ECM accumulation in podocytes.

• 影响指数: 3.568
• 发表时间: Mar 2021
• 来源期刊: J Biochem Mol Toxicol
• DOI: 10.1002/jbt.22672
• PMID: 33270355
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 生物
• 作者列表: Yan H,Xu F,Xu J,Song MA,Wang K,Wang L

关键词: Brg-1; Nrf2/ARE signaling; diabetic nephropathy; extracellular matrix accumulation; oxidative stress

Mesh: Animals; Antioxidant Response Elements; Cell Line, Transformed; DNA Helicases / genetics metabolism; Extracellular Matrix / genetics metabolism; Extracellular Matrix Proteins / genetics metabolism; Glucose / pharmacology; Mice; NF-E2-Related Factor 2 / genetics metabolism; Nuclear Proteins / genetics metabolism; Oxidative Stress / drug effects; Podocytes / metabolism pathology; Proto-Oncogene Proteins c-akt / genetics metabolism; Signal Transduction / drug effects; Transcription Factors / genetics metabolism

Abstract

Brahma-related gene 1 (Brg-1) is perceived as a cytoprotective protein due to its role in alleviating oxidative stress and apoptosis. Our study aimed to explore the role and mechanism of Brg-1 in high glucose (HG)-stimulated podocytes. The HG exposure downregulated Brg-1 and inactivated the protein kinase B (Akt) pathway in podocytes. Restoration of Brg-1 inhibited HG-induced viability reduction of podocytes. The HG-induced increase of reactive oxygen species and malondialdehyde levels and decrease of superoxide dismutase activity in podocytes were reversed by the Brg-1 overexpression. The Brg-1 overexpression terminated the HG-induced production of fibronectin, collagen IV, transforming growth factor-β1, and connective tissue growth factor. In addition, the Brg-1 overexpression activated Akt-dependent nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling in HG-stimulated podocytes. However, inhibition of the Akt pathway or Nrf2 silencing counteracted the protective effects of Brg-1 in HG-stimulated podocytes. In conclusion, the Brg-1 overexpression suppressed HG-induced oxidative stress and extracellular matrix accumulation by activation of Akt-dependent Nrf2/ARE signaling in podocytes.