title: Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating CKIP-1 to resist HG-induced up-regulation of FN and ICAM-1 in GMCs and diabetic mice kidneys.
abstract: Our previous study indicated that Casein kinase 2 interacting protein-1 (CKIP-1) could promote the activation of the nuclear factor E2-related factor 2 (Nrf2)/ antioxidant response element (ARE) pathway, playing a significant role in inhibiting the fibrosis of diabetic nephropathy (DN). Polydatin (PD) has been shown to possess strong resistance effects on renal fibrosis which is closely related to activating the Nrf2/ARE pathway, too. Whereas, whether PD could resist DN through regulating CKIP-1 and consequently promoting the activation of Nrf2-ARE pathway needs further investigation. Here, we found that PD significantly reversed the down-regulation of CKIP-1 and attenuated fibronectin (FN) and intercellular cell adhesion molecule-1 (ICAM-1) in glomerular mesangial cells (GMCs) exposed to high glucose (HG). Moreover, PD could decrease Keap1 expression and promote the nuclear content, ARE-binding ability, and transcriptional activity of Nrf2. The activation of Nrf2-ARE pathway by PD eventually led to the quenching of hydrogen peroxide (H2O2) and superoxide overproduction boosted by HG. Depletion of CKIP-1 blocked the Nrf2-ARE pathway activation and reversed FN and ICAM-1 down-regulation induced by PD in GMCs challenged with HG. PD increased CKIP-1 and Nrf2 levels in the kidney tissues as well as improved the anti-oxidative effect and renal dysfunction of diabetic mice, which eventually reversed the up-regulation of FN and ICAM-1. Experiments above suggested that PD could increase the CKIP-1-Nrf2-ARE pathway activation to prevent the OSS-induced insult in GMCs and diabetic mice which effectively postpone the diabetic renal fibrosis and the up-regulation of CKIP-1 is probably a novel mechanism in this process.
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Gong
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: Li
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Zhiquan
authors.initials: Z
authors.lastname: Chen
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: Qiuhong
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Guangdong Engineering & Technology Research Center for Disease-Model Animals, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Cai
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, 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; Guangdong Engineering & Technology Research Center for Disease-Model Animals, Sun Yat-sen University, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, 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; D000975:Antioxidants / Q000008:administration & dosage; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005353:Fibronectins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D005960:Glucosides / Q000008:administration & dosage; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000008:administration & dosage; D013481:Superoxides / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins
chemical_list: D000975:Antioxidants; D002265:Carboxylic Ester Hydrolases; D002352:Carrier Proteins; D005353:Fibronectins; D005947:Glucose; D005960:Glucosides; D006861:Hydrogen Peroxide; D018799:Intercellular Adhesion Molecule-1; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D013267:Stilbenes; D013481:Superoxides; C117301:Keap1 protein, mouse; C495636:Nfe2l2 protein, mouse; C019734:arylesterase; C058229:polydatin; C000620556:PLEKHO1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins
keywords: CKIP-1; Diabetic nephropathy; Keap1; Nrf2/ARE pathway; Oxidative stress; Polydatin