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

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.

Local complement factor H protects kidney endothelial cell structure and function

“…FH is present in the glomerulus and microvasculature (arrow). This is in line with our earlier results 40 and that of several others such as Zoshima et al 41 and Chen et al, 35 revealing the expression of FH in the glomerulus.…”

“…34 Further, studies reveal that cadmium increases the expression of FH in glomerular EnCs through c-Jun N-terminal kinase signaling. 35 In addition, FH in the glomeruli partially colocalized with CD31 in hepatic FH-deficient mice, showing endothelial presence. 36 Our studies for the first time show that the absence of intrinsic FH alters gene expression in cultured kidney EnCs (KEnCs).…”

Gastric cancer–secreted exosomal X26nt increases angiogenesis and vascular permeability by targeting VE‐cadherin

“…The immunofluorescence was performed by staining with a rabbit polyclonal antibody against human/mouse VE-Cadherin (1:200; ab33168, Abcam) and a Goat Anti-Rabbit IgG H&L (Alexa Fluor 488) (1:200; ab150077, Abcam) as previously described. 27 Then cells were mounted with ProLong® Gold antifade Reagent with DAPI (Life Technologies). Images were captured using Leica SP5 Laser scanning confocal microscope.…”

Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis

“…Exploring the mRNA expression for Cfh in the kidney showed that the expression was identical in the WT and hepatoFH −/− mice and was not affected by PHZ injection (Figure 5B). Exploring of FH staining in mouse kidney has been tricky and previous studies failed to detect it despite the clear evidence for mRNA production by various renal cell populations (26)(27)(28)(29)(30)(31). The reason for this lack of staining in previous studies vs. the positive staining detected here is unclear and is likely related to the experimental conditions.…”