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Upregulation of allograft inflammatory factor1 expression and secretion by macrophages stimulated with aldosterone promotes renal fibroblasts to a profibrotic phenotype

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Macrophages have been identified as a key cell type in the pathogenesis of renal interstitial fibrosis (RIF). However, the mechanism through which macrophages drive fibrosis remains unclear. The current study focuses on the effects and possible underlying mechanism of allograft inflammatory factor1 (AIF1), an inflammationresponsive scaffold protein expressed and secreted by macrophages, in promoting fibroblasts to a profibrotic phenotype. In vivo experiments indicated that AIF1, CD68 and αsmooth muscle actin (αSMA) were upregulated in kidney tissues of mice subjected to unilateral ureteric obstruction, while their expressions were inhibited by an aldosterone receptor antagonist, spironolactone. Double immunofluorescence staining revealed that AIF1 expression colocalized with CD68positive macrophages in the renal interstitium, indicating that AIF1 expression in macrophages was increased in the RIF animal model. Furthermore, to identify the role of AIF1 in promoting fibrosis, its expression and secretion by the RAW264.7 macrophage cell line were detected in vitro. The expression levels of αSMA, phosphorylated p38 (pp38) and fibronectin (FN) in fibroblasts were examined subsequent to coculture with macrophages. The increase in AIF1 expression and secretion was confirmed in RAW264.7 cells in response to aldosterone. After 72 h of coculture between fibroblasts and macrophages stimulated with aldosterone, the αSMA expression was induced in fibroblasts, with significantly increased expression levels of FN and pp38 observed. In addition, AIF1 expression was reduced by stable transfection of RAW264.7 cells with AIF1 small interfering RNA, resulting in significantly reduced expression levels of αSMA, pp38 and FN in fibroblasts cocultured with macrophages as compared with normal macrophages. These findings indicate that the expression of AIF1 in macrophages is critical for the activation of renal fibroblasts to a profibrotic phenotype. AIF1 expression was upregulated in macrophages, and may be a novel mechanism linking macrophages to the promotion of RIF via the p38 signaling pathway.
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Document Type: Research Article

Affiliations: Department of Nephropathy, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China

Publication date: January 1, 2018

More about this publication?
  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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