title: CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells.
abstract: Glucose and lipid metabolism disorders as well as oxidative stress (OSS) play important roles in diabetic nephropathy (DN). Glucose and lipid metabolic dysfunctions are the basic pathological changes of chronic microvascular complications of diabetes mellitus, such as DN. OSS can lead to the accumulation of extracellular matrix and inflammatory factors which will accelerate the progress of DN. Casein kinase 2 interacting protein-1 (CKIP-1) mediates adipogenesis, cell proliferation and inflammation under many circumstances. However, whether CKIP-1 is involved in the development of DN remains unknown. Here, we show that CKIP-1 is a novel regulator of resisting the development of DN and the underlying molecular mechanism is related to activating the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidative stress pathway. The following findings were obtained: (1) The treatment of glomerular mesangial cells (GMCs) with high glucose (HG) decreased CKIP-1 levels in a time-dependent manner; (2) CKIP-1 overexpression dramatically reduced fibronectin (FN) and intercellular adhesionmolecule-1 (ICAM-1) expression. Depletion of CKIP-1 further induced the production of FN and ICAM-1; (3) CKIP-1 promoted the nuclear accumulation, DNA binding, and transcriptional activity of Nrf2. Moreover, CKIP-1 upregulated the expression of Nrf2 downstream genes, heme oxygenase (HO-1) and superoxide dismutase 1 (SOD1); and ultimately decreased the levels of reactive oxygen species (ROS). The molecular mechanisms clarify that the advantageous effect of CKIP-1 on DN are well connected with the activation of the Nrf2/ARE antioxidative stress pathway.
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, 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, 132 East Circle at University Town, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, 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; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China.
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University Town, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China.
authors.forename: Yu
authors.initials: Y
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; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, 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, 132 East Circle at University Town, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, 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; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China. Electronic address: huangheq@mail.sysu.edu.cn.
authors.forename: Heqing
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D021581:Active Transport, Cell Nucleus; D061745:Antioxidant Response Elements; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000378:metabolism; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D013047:Specific Pathogen-Free Organisms; D047908:Intracellular Signaling Peptides and Proteins
chemical_list: D002352:Carrier Proteins; D005353:Fibronectins; C090509:Icam1 protein, mouse; C000609942:ICAM1 protein, rat; D018799:Intercellular Adhesion Molecule-1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D011994:Recombinant Proteins; C000620534:PLEKHO1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins
keywords: CKIP-1; Diabetic nephropathy; Keap1; Nrf2/ARE pathway; Oxidative stress