Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-尾1 by activating the Nrf2/ARE pathway in glomerular mesangial cells

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• 作者：Kaipeng Huang ; Juan Huang ; Xi Xie ; Shaogui Wang ; Cheng Chen ; Xiaoyan Shen ; Peiqing Liu ; Heqing Huang
• 关键词：AGEs ; advanced glycation end products ; ARE ; antioxidant response element ; BSA ; bovine serum albumin ; DN ; diabetic nephropathy ; ECM ; extracellular matrix ; EMSA ; electrophoretic mobility shift assay ; FN ; fibronectin ; GMCs ; glomerular messangial cells ; HO-1 ; heme oxygenase 1 ; Keap1 ; kelch like ECH-associated protein 1 ; MAPK ; mitogen-activated protein kinase ; MDA ; malonaldehyde ; MnSOD ; manganese superoxide dismutase ; NAD+ ; nicotinamide adenosine dinucleotide+ ; Nrf2 ; nuclear factor E2-related factor
• 刊名：Free Radical Biology and Medicine
• 出版年：December, 2013
• 年：2013
• 卷：65
• 期：Complete
• 页码：528-540
• 全文大小：5668 K

文摘

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-尾1 (TGF-尾1) 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-尾1 levels in a dose- and time-dependent manner; (2) resveratrol or Sirt1 overexpression markedly increased Sirt1 levels and reduced FN and TGF-尾1 expressions; (3) inhibition of Sirt1 activity further induced the productions of FN and TGF-尾1; (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-尾1 in the kidneys of diabetic rats. This work supports a negative role of Sirt1 in AGE-induced overproductions of FN and TGF-尾1. The molecular mechanisms that underlie the beneficial effects of Sirt1 on DN correlate well with the activation of the Nrf2/ARE antioxidative pathway.