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Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-β1 by activating the Nrf2/ARE pathway in glomerular mesangial cells.
Free Radic Biol Med. 2013 Dec; 65:528-540.FR

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+Show Affiliations

Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou, 510006, China.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23891678

Citation

Huang, Kaipeng, et al. "Sirt1 Resists Advanced Glycation End Products-induced Expressions of Fibronectin and TGF-β1 By Activating the Nrf2/ARE Pathway in Glomerular Mesangial Cells." Free Radical Biology & Medicine, vol. 65, 2013, pp. 528-540.
Huang K, Huang J, Xie X, et al. Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-β1 by activating the Nrf2/ARE pathway in glomerular mesangial cells. Free Radic Biol Med. 2013;65:528-540.
Huang, K., Huang, J., Xie, X., Wang, S., Chen, C., Shen, X., Liu, P., & Huang, H. (2013). Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-β1 by activating the Nrf2/ARE pathway in glomerular mesangial cells. Free Radical Biology & Medicine, 65, 528-540. https://doi.org/10.1016/j.freeradbiomed.2013.07.029
Huang K, et al. Sirt1 Resists Advanced Glycation End Products-induced Expressions of Fibronectin and TGF-β1 By Activating the Nrf2/ARE Pathway in Glomerular Mesangial Cells. Free Radic Biol Med. 2013;65:528-540. PubMed PMID: 23891678.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-β1 by activating the Nrf2/ARE pathway in glomerular mesangial cells. AU - Huang,Kaipeng, AU - Huang,Juan, AU - Xie,Xi, AU - Wang,Shaogui, AU - Chen,Cheng, AU - Shen,Xiaoyan, AU - Liu,Peiqing, AU - Huang,Heqing, Y1 - 2013/07/24/ PY - 2013/01/22/received PY - 2013/06/20/revised PY - 2013/07/19/accepted PY - 2013/7/30/entrez PY - 2013/7/31/pubmed PY - 2015/8/8/medline KW - AGEs KW - ARE KW - Advanced glycation end products KW - BSA KW - DN KW - Diabetic nephropathy KW - ECM KW - EMSA KW - FN KW - GMCs KW - HO-1 KW - Keap1 KW - MAPK KW - MDA KW - MnSOD KW - NAD(+) KW - Nrf2 KW - Nrf2/ARE pathway KW - OSS KW - Oxidative stress KW - PKC KW - ROS KW - RSV KW - STZ KW - Sirt1 KW - TGF-β1 KW - advanced glycation end products KW - antioxidant response element KW - bovine serum albumin KW - diabetic nephropathy KW - electrophoretic mobility shift assay KW - extracellular matrix KW - fibronectin KW - glomerular messangial cells KW - heme oxygenase 1 KW - kelch like ECH-associated protein 1 KW - malonaldehyde KW - manganese superoxide dismutase KW - mitogen-activated protein kinase KW - nicotinamide adenosine dinucleotide(+) KW - nuclear factor E2-related factor 2 KW - oxidative stress KW - protein kinase C KW - reactive oxygen species KW - resveratrol KW - streptozocin KW - transforming growth factor-β1 SP - 528 EP - 540 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 65 N2 - 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. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/23891678/Sirt1_resists_advanced_glycation_end_products_induced_expressions_of_fibronectin_and_TGF_β1_by_activating_the_Nrf2/ARE_pathway_in_glomerular_mesangial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(13)00373-0 DB - PRIME DP - Unbound Medicine ER -