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J Immunol. 2019 Feb 15;202(4):1210-1218. doi: 10.4049/jimmunol.1800081. Epub 2019 Jan 14.

Cadmium Induces Glomerular Endothelial Cell-Specific Expression of Complement Factor H via the -1635 AP-1 Binding Site.

Author information

1
Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China.
2
Department of Epidemiology and Public Health, Yale University, New Haven, CT 06520; and.
3
Department of Biology, Trent University, Peterborough, Ontario K9L 0G2, Canada.
4
Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China; ju.liu@sdu.edu.cn.

Abstract

Cadmium (Cd) is an environmental toxin that induces nephrotoxicity. Complement factor H (CFH), an inhibitor of complement activation, is involved in the pathogenesis of various renal diseases. In this study, we investigated the effects of Cd on CFH production by the kidney. In C57B6/J mice, an increased CFH level was found in renal blood and glomerular endothelial cells after Cd treatment. In vitro, Cd induces an increased CFH secretion and mRNA expression in human renal glomerular endothelial cells but not in human podocytes or human mesangial cells. Cd activates the JNK pathway and increases c-Jun and c-Fos in human renal glomerular endothelial cells. A JNK inhibitor, SP600125, specifically abolishes Cd-induced CFH production. By chromatin immunoprecipitation assay and EMSA, the -1635 AP-1 motif on human CFH promoter was identified as the binding element for c-Jun and c-Fos. In a luciferase activity assay, mutation of the AP1 site eliminates Cd-induced increase of CFH promoter activity. Thus, the -1635 AP-1 motif on the CFH promoter region mediates Cd-inducible CFH gene expression.

PMID:
30642982
DOI:
10.4049/jimmunol.1800081

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