title: Targeting JNK by a new curcumin analog to inhibit NF-kB-mediated expression of cell adhesion molecules attenuates renal macrophage infiltration and injury in diabetic mice.
abstract: Macrophage infiltration contributes to the pathogenesis of diabetic renal injury. However, the regulatory mechanisms between macrophage infiltration and epithelial cell activation are still unclear. Our previous study found that C66, a novel curcumin analog, was able to inhibit inflammatory cytokine expression in vitro and in vivo. This study further elucidated whether C66 can prevent glucose-induced renal epithelial activation and inflammatory macrophage infiltration by a MAPK/NF-κB medicated mechanism. Our data show that pretreatment with C66 not only significantly reduced high glucose (HG)-induced over-expressions of VCAM-1, ICAM-1 and MCP-1, but also remarkably inhibited NF-κB activation, MAPKs phosphorylation, and subsequently macrophage adhesion in renal epithelial NRK-52E cells. Furthermore, we find that MAPKs, especially JNK, play important roles in HG-induced NF-κB activation, which regulates the over-expression of adhesion molecules in HG-stimulated NRK-52E cells. A molecular docking predicted that C66 may target JNK2, which leads to its anti-inflammatory actions. In vivo, administration of C66 or JNK special inhibitor SP600125 at 5 mg/kg markedly decreased diabetes-induced renal adhesion molecule expression, NF-κB activation, inflammatory cell infiltration, and pathological indexes in the kidneys of diabetic mice. These findings provide a perspective on the renoprotective effects of C66 in diabetes, and outline a novel therapeutic strategy of JNK inhibition for the treatment of diabetic nephropathy.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China ; Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
authors.forename: Luqing
authors.initials: L
authors.lastname: Ren
authors.forename: Longguang
authors.initials: L
authors.lastname: Tang
authors.forename: Jingying
authors.initials: J
authors.lastname: Wang
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Wang
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
chemical_list: D000873:Anthracenes; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; C090509:Icam1 protein, mouse; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C432165:pyrazolanthrone; D048670:MAP Kinase Kinase 4; D003474:Curcumin