Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-β1 by activating the Nrf2/ARE pathway in glomerular mesangial cells

摘要

Advanced glycation end products (AGEs) boost the generation of reactive oxygen species (ROS) in glomerular mesangial cells (GMCs), and thereby play important roles in diabetic nephropathy (DN). Sirtuin 1 (Sirt1), a protein deacetylase, is known to markedly protect cells from oxidative stress (OSS) injury. Based on the critical involvements of AGEs and Sirt1 in OSS, Sirt1 is postulated to resist AGEs-induced diabetic renal fibrosis through its antioxidative effects. The current study was designed to explore the inhibitory effect of Sirt1 on the expressions of fibronectin (FN) and transforming growth factor-β1 (TGF-β1) induced by AGEs in GMCs. The molecular mechanism by which Sirt1 promoted the activation of the antioxidative pathway was further investigated. The following findings were obtained: (1) the treatment of GMCs with AGEs decreased Sirt1 levels in terms of protein expression and activity but increased FN and TGF-β1 levels in a dose- and time-dependent manner; (2) resveratrol or Sirt1 overexpression markedly increased Sirt1 levels and reduced FN and TGF-β1 expressions; (3) inhibition of Sirt1 activity further induced the productions of FN and TGF-β1; (4) Sirt1 promoted the nuclear accumulation, DNA binding, and transcriptional activities of Nrf2 and upregulated the expressions of Nrf2 downstream genes, heme oxygenase-1, and superoxide dismutase 1; ROS levels induced by AGEs eventually reduced in a deacetylase-dependent manner; and (5) with the deposition of AGEs in the kidneys, the diabetic rats suffered severe renal dysfunction and high OSS levels; resveratrol treatment evidently diminished the OSS levels, ameliorated renal injury, and prevented the expressions of FN and TGF-β1 in the kidneys of diabetic rats. This work supports a negative role of Sirt1 in AGE-induced overproductions of FN and TGF-β1. The molecular mechanisms that underlie the beneficial effects of Sirt1 on DN correlate well with the activation of the Nrf2/ARE antioxidative pathway.