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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anthracenes / pharmacology
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Cell Line
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Chemokine CCL2 / biosynthesis
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Curcumin* / analogs & derivatives
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Curcumin* / pharmacology
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / pathology
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Diabetic Nephropathies / drug therapy*
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Diabetic Nephropathies / metabolism
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Diabetic Nephropathies / pathology
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Enzyme Inhibitors / pharmacology*
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Gene Expression Regulation / drug effects*
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Intercellular Adhesion Molecule-1 / biosynthesis*
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MAP Kinase Kinase 4 / antagonists & inhibitors*
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MAP Kinase Kinase 4 / metabolism
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MAP Kinase Signaling System / drug effects*
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Male
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Mice
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NF-kappa B / metabolism*
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Phosphorylation / drug effects
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Vascular Cell Adhesion Molecule-1 / biosynthesis*
Substances
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Anthracenes
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Ccl2 protein, mouse
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Chemokine CCL2
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Enzyme Inhibitors
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Icam1 protein, mouse
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NF-kappa B
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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pyrazolanthrone
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MAP Kinase Kinase 4
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Curcumin
Grants and funding
This study was supported by the National “863” key project [Grant 2011AA 02A 113]; Natural Science Funding of China [Grants 81261120560, 81072683, 81302821, 81173140, and 81200572]; High-level Innovative Talent Funding of Zhejiang Department of Health [to GL], Zhejiang provincial Natural Science Funding [Grants LQ13H310002], a start-up fund for the Chinese-American Research Institute for Diabetic Complications from Wenzhou Medical College [to LC], and Zhejiang Key Group in Scientific Innovation (2010R50042 to XL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.