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

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.