title: Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-β1 by activating the Nrf2/ARE pathway in glomerular mesangial cells.
abstract: 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.
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.
authors.forename: Kaipeng
authors.initials: K
authors.lastname: Huang
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Huang
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Xie
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.
authors.forename: Shaogui
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shen
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China. Electronic address: huangheq@mail.sysu.edu.cn.
authors.forename: Heqing
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005353:Fibronectins / Q000096:biosynthesis*; D005455:Fluorescent Antibody Technique; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000378:metabolism*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*
chemical_list: D005353:Fibronectins; D017127:Glycation End Products, Advanced; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D053773:Transforming Growth Factor beta1; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
keywords: AGEs; ARE; Advanced glycation end products; BSA; DN; Diabetic nephropathy; ECM; EMSA; FN; GMCs; HO-1; Keap1; MAPK; MDA; MnSOD; NAD(+); Nrf2; Nrf2/ARE pathway; OSS; Oxidative stress; PKC; ROS; RSV; STZ; Sirt1; TGF-β1; advanced glycation end products; antioxidant response element; bovine serum albumin; diabetic nephropathy; electrophoretic mobility shift assay; extracellular matrix; fibronectin; glomerular messangial cells; heme oxygenase 1; kelch like ECH-associated protein 1; malonaldehyde; manganese superoxide dismutase; mitogen-activated protein kinase; nicotinamide adenosine dinucleotide(+); nuclear factor E2-related factor 2; oxidative stress; protein kinase C; reactive oxygen species; resveratrol; streptozocin; transforming growth factor-β1