title: Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating Sirt1 to resist AGEs-induced upregulation of fibronetin and transforming growth factor-β1 in rat glomerular messangial cells.
abstract: Sirt1 and nuclear factor-E2 related factor 2 (Nrf2)-anti-oxidant response element (ARE) anti-oxidative pathway play important regulatory roles in the pathological progression of diabetic nephropathy (DN) induced by advanced glycation-end products (AGEs). Polydatin (PD), a glucoside of resveratrol, has been shown to possess strong anti-oxidative bioactivity. Our previous study demonstrated that PD markedly resists the progression of diabetic renal fibrosis and thus, inhibits the development of DN. Whereas, whether PD could resist DN through regulating Sirt1 and consequently promoting Nrf2-ARE pathway needs further investigation. Here, we found that concomitant with decreasing RAGE (the specific receptor for AGEs) expression, PD significantly reversed the downregulation of Sirt1 in terms of protein expression and deacetylase activity and attenuated FN and TGF-β1 expression in GMCs exposed to AGEs. Under AGEs-treatment condition, PD could decrease Keap1 expression and promote the nuclear content, ARE-binding ability, and transcriptional activity of Nrf2. In addition, PD increased the protein levels of heme oxygenase 1 (HO-1) and superoxide dismutase 1 (SOD1), two target genes of Nrf2. The activation of Nrf2-ARE pathway by PD eventually led to the quenching of ROS overproduction sharply boosted by AGEs. Depletion of Sirt1 blocked Nrf2-ARE pathway activation and reversed FN and TGF-β1 downregulation induced by PD in GMCs challenged with AGEs. Along with reducing HO-1 and SOD1 expression, silencing of Nrf2 increased FN and TGF-β1 levels. PD treatment elevated Sirt1 and Nrf2 levels in the kidney tissues of diabetic rats, then improved the anti-oxidative capacity and renal dysfunction of diabetic models, and finally reversed the upregulation of FN and TGF-β1. Taken together, the resistance of PD on upregulated FN and TGF-β1 induced by AGEs via oxidative stress in GMCs is closely associated with its activation of Sirt1-Nrf2-ARE pathway.
authors.affiliation: Department of Pharmacy, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 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, 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, Guangzhou 510006, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hao
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Junying
authors.initials: J
authors.lastname: Huang
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 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, 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, Guangzhou 510006, China. Electronic address: huangheq@mail.sysu.edu.cn.
authors.forename: Heqing
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics; D020868:Gene Silencing; D005960:Glucosides / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D005353:Fibronectins; D005960:Glucosides; D017127:Glycation End Products, Advanced; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013267:Stilbenes; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C058229:polydatin
keywords: Advanced glycation-end products; Diabetic nephropathy; Nrf2-ARE pathway; Oxidative stress; Polydatin; Sirt1