Progestin and AdipoQ Receptor 3 Upregulates Fibronectin and Intercellular Adhesion Molecule-1 in Glomerular Mesangial Cells via Activating NF-κB Signaling Pathway Under High Glucose Conditions.
Progestin and AdipoQ Receptor 3 Upregulates Fibronectin and Intercellular Adhesion Molecule-1 in Glomerular Mesangial Cells via Activating NF-κB Signaling Pathway Under High Glucose Conditions.
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DOI：
10.3389/fendo.2018.00275
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发表时间：
2018
影响因子：
5.2
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Zou Y;Chen Z;Li J;Gong W;Zhang L;Xu F;Chen L;Liu P;Huang H
黄体酮和脂肪q受体3 （PAQR3）是一种高尔基锚定膜蛋白，含有7个跨膜螺旋。研究表明，PAQR3介导胰岛素抵抗、糖脂代谢和炎症。此外，肾脏炎性纤维化是糖尿病肾病（DN）的重要病理特征。因此，我们旨在研究PAQR3在糖尿病肾纤维化和DN炎症中的作用。研究PAQR3对高糖培养的肾小球系膜细胞（GMCs） NF-κB信号通路、纤连蛋白（FN）和细胞间粘附分子-1 （ICAM-1）表达的影响。采用链脲佐菌素（STZ）诱导糖尿病小鼠和大鼠模型。用HG处理GMCs，转染PAQR3质粒或靶向PAQR3或NF-κB的小干扰RNA。Western blotting检测FN和ICAM-1蛋白表达水平，双荧光素酶报告基因法和电泳迁移转移法（EMSA）检测NF-κB转录活性和DNA结合活性。采用共免疫沉淀法分析PAQR3与核因子κB激酶β抑制剂IKKβ的相互作用。在stz诱导的糖尿病模型和hg处理的gmc中，PAQR3均升高。PAQR3过表达进一步增加hg诱导的FN和ICAM-1上调。相反，PAQR3的沉默抑制了FN和ICAM-1的表达。PAQR3过表达可促进NF-κB的核积累、DNA结合活性和转录活性。机械上，PAQR3直接与IKKβ相互作用。PAQR3过表达对hg处理的GMCs中FN和ICAM-1表达的上调作用被NF-κB siRNA或PDTC（吡咯烷二硫代氨基甲酸铵）处理消除。PAQR3通过激活NF-κB信号通路促进FN和ICAM-1的表达。在机制上，PAQR3通过与DN中IKKβ的直接相互作用，激活NF-κB信号通路介导肾炎性纤维化。
Progestin and adipoQ receptor 3 (PAQR3), is a Golgi-anchored membrane protein containing seven transmembrane helices. It has been demonstrated that PAQR3 mediates insulin resistance, glucose and lipid metabolism, and inflammation. In addition, kidney inflammatory fibrosis is an important pathological feature of diabetic nephropathy (DN). Therefore, we aimed to investigate the role of PAQR3 in diabetic kidney fibrosis as well as inflammation in DN. The effect of PAQR3 on NF-κB signaling pathway, expressions of fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1) in glomerular mesangial cells (GMCs) cultured by high glucose (HG) were examined. Diabetic mouse and rat models were induced by streptozotocin (STZ). GMCs were treated with HG and transfected with PAQR3 plasmids or small-interfering RNA targeting PAQR3 or NF-κB. The protein levels of FN and ICAM-1 were examined by Western blotting, and the transcriptional activity and DNA binding activity of NF-κB were measured by dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The interaction between PAQR3 and IKKβ (inhibitor of nuclear factor κB kinase β) was analyzed by co-immunoprecipitation. PAQR3 was increased in both STZ-induced diabetic models and HG-treated GMCs. PAQR3 overexpression further increased HG-induced FN and ICAM-1 upregulation. In contrast, silencing of PAQR3 suppressed the expressions of FN and ICAM-1. PAQR3 overexpression promoted the nuclear accumulation, DNA binding activity, and transcriptional activity of NF-κB. Mechanically, PAQR3 directly interacted with IKKβ. The upregulation effect of PAQR3 overexpression on the expressions of FN and ICAM-1 was abolished by the treatment of NF-κB siRNA or PDTC (ammonium pyrrolidinedithiocarbamate) in HG-treated GMCs. PAQR3 promotes the expressions of FN and ICAM-1 via activating NF-κB signaling pathway. Mechanistically, PAQR3 activates NF-κB signaling pathway to mediate kidney inflammatory fibrosis through direct interaction with IKKβ in DN.