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

详细信息    查看全文

• 作者：Wenyan Gong ; Cheng Chen ; Fengxiao Xiong ; Zhiying Yang ; Yu Wang ; Junying Huang ; Peiqing Liu ; Heqing Huang ; ^{huangheq@mail.sysu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ARE ; antioxidant response element ; CKIP-1 ; Casein Kinase 2-Interacting Protein-1 ; DN ; diabetic nephropathy ; FN ; fibronectin ; HO-1 ; heme oxygenase 1 ; ICAM-1 ; intercellular adhesionmolecule-1 ; Keap1 ; kelch like ECH-associated protein 1 ; MnSOD ; manganese superoxide dismutase ; NAD+ ; nicotinamide adenosine dinucleotide + ; Nrf2 ; nuclear factor E2-related factor 2 ; OSS ; oxidative stress ; ROS ; reactive oxygen species ; SOD ; superoxide dismutase ; HG ; high glucose ; NG ; normal glucose
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：116
• 期：Complete
• 页码：140-152
• 全文大小：3204 K

文摘

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.