ArticleMolecular vision2025
Hyperosmolar stress induces monocyte chemoattractant protein 1 expression in retinal pigmented epithelial arising retinal pigmented epithelial 19 cells.
Article in Molecular vision, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: Diabetes is a chronic inflammatory disease that may damage the blood-retinal barrier, leading to diabetic retinopathy (DR). Blood-retinal barrier rupture may subject the retinal pigmented epithelial cells to a hyperosmolar stress (HOS), activating the transcription factor nuclear factor of activated T cells 5 (NFAT5). In addition, inflammatory cytokines, such as monocyte chemoattractant protein 1 (MCP-1/CCL2), play a crucial role in DR. The aims of our study were to determine whether HOS induces MCP-1 levels in arising retinal pigmented epithelial 19 (ARPE-19) cells and to decipher the responsible intracellular cascade involved in such stimulation. Methods: ARPE-19 cells or ARPE-19 cells transfected with dominant negative NFAT5 plasmid or NFAT5 short hairpin RNA plasmids were preincubated or not for 1 h in the absence or presence of a protein kinase or transcription factor inhibitor and then incubated for 8 h with iso-osmolar or hyperosmolar medium in the absence or presence of inhibitor. NFAT5 reporter gene activity was quantified by luminescence. MCP-1 messenger RNA (mRNA) and protein levels were determined by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. Biologically active MCP-1 was assessed by a calcium mobilization assay performed using Chinese hamster ovary cells expressing or not the MCP-1 receptor and apoaequorin. Results: In response to HOS, ARPE-19 cells showed a significant increase in MCP-1 mRNA levels independent of NFAT5 activation. Moreover, the MCP-1 protein secreted by ARPE-19 in response to HOS is biologically active. The use of various inhibitors of protein kinase and transcription factors suggest that the HOS-induced increase in MCP-1 mRNA levels is dependent on a protein kinase C (PKC) and/or a MEK1/2-p38 pathway activating p53, as well as a PKC-p38-PI3K-PDK1-AKT activating hypoxia-inducible factor 1 alpha (HIF1α). Conclusion: HOS increases the expression of MCP-1 mRNA and protein levels in ARPE-19 cells, and the secreted MCP-1 is biologically active. The HOS-induced increase of MCP-1 mRNA appears to be independent of NFAT5 activation. Despite the activation of NFAT5 upon HOS and the presence of NFAT5 binding sites in the MCP-1 gene promoter, activated NFAT5 may not be sufficient to induce MCP-1 gene transactivation in response to HOS in ARPE-19 cells. The intracellular cascade involved in the HOS-induced increase of MCP-1 mRNA in ARPE-19 cells may consist of a PKC-p38-PI3K-PDK1-AKT-HIF1α axis and/or a MEK1/2-p38-p53 axis.
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Identifiers
41867363PMC13002342What Socratic holds
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