title: Connexin43 regulates high glucose-induced expression of fibronectin, ICAM-1 and TGF-β1 via Nrf2/ARE pathway in glomerular mesangial cells.
abstract: Nrf2/ARE signaling pathway is a crucial cellular defense system to cope with oxidative stress, which is adaptively activated, in diabetic condition that is not efficient enough to resist the oxidative stress provoked by hyperglycemia. We have previously demonstrated that Connexin43 (Cx43) attenuates renal fibrosis through c-Src. However, the underlying mechanisms need to be further clarified. It has been reported that Cx43 possesses the ability of anti-oxidative. The current study aimed to determine if Cx43 exerts protective effects on renal fibrosis in diabetes via activation of Nrf2/ARE pathway and explore the underlying molecular mechanisms. The following findings were observed: (1) Cx43 expression decreased and c-Src activity increased in kidneys of diabetic animals; (2) Over-expressed Cx43 in high glucose treated GMCs inhibited protein levels of FN, ICAM-1 and TGF-β1; (3) Nrf2/ARE signaling adaptively responded to high glucose treatment in GMCs; (4) Cx43 reduced ROS generation by boost Nrf2/ARE signaling under high glucose condition; (5) Inhibition of c-Src activity promoted nucleus accumulation of Nrf2; (6) Over-expressed Cx43 inhibited c-Src activity and the interaction between c-Src and Nrf2 in GMCs cultured in high glucose. Thus we propose that Cx43 might enhance the activation of Nrf2/ARE pathway by means of inhibiting c-Src activity to hinder the nuclear export of Nrf2, and then reduce expression of FN, ICAM-1 and TGF-β1, ultimately attenuating renal fibrosis in diabetes.
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: Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China; Department of Pharmaceutical Sciences, College of Marine Science, Hainan University, Haikou 570228, China. Electronic address: xiaprilxie@berkeley.edu.
authors.forename: Xi
authors.initials: X
authors.lastname: Xie
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: Wenyan
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Pharmaceutical Sciences, College of Marine Science, Hainan University, Haikou 570228, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhu
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: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jiani
authors.initials: J
authors.lastname: Huang
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; D000975:Antioxidants / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002265:Carboxylic Ester Hydrolases / Q000235:genetics; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D051381:Rats; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: D000975:Antioxidants; D018031:Connexin 43; C067625:FN1 protein, human; D005353:Fibronectins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D005947:Glucose
keywords: Connexin43; Diabetic nephropathy; Nrf2/ARE pathway; Oxidative stress; Renal fibrosis; c-Src