Journal
NEPHROLOGY
Volume 22, Issue 2, Pages 150-158Publisher
WILEY-BLACKWELL
DOI: 10.1111/nep.12746
Keywords
peritoneal dialysis; IL-6 trans-signalling; vascular endothelial growth factor; JAK; STAT3
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Funding
- National Nature Science Foundation Grant of China [81370864]
- Science and Technology Commission of Shanghai Municipality [07QA14040, 08dz1900500, 114119a5900]
- 5th Asia Pacific PD College Research Grant
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AimsInterleukin-6 (IL-6) is a vital inflammatory factor in the peritoneal cavity of peritoneal dialysis (PD) patients. Because intraperitoneal inflammation is closely associated with angiogenesis, we sought to explore the effect of IL-6 on vascular endothelial growth factor (VEGF) synthesis and its transduction pathway in mesothelial cells. MethodsHuman mesothelial cells (Met-5A) were incubated with different concentrations of glucose and mannitol, and the effect of glucose and mannitol on the expression of IL-6 was determined. Then, the cells were stimulated by IL-6 with or without two soluble receptors of IL-6 (sIL-6R or sgp130), and VEGF synthesis was detected. Finally, the cells were incubated with IL-6/sIL-6R combined with or without the inhibitor of Janus kinases (JAK) AG490. The phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and its intracellular translocation were examined. Results1. High glucose and mannitol could upregulate IL-6 mRNA expression and IL-6 secretion in mesothelial cells significantly, and there was no difference of its effect between high glucose and mannitol. 2. Met-5A was a cell line with a single IL-6 receptor. The IL-6/sIL-6R complex induced VEGF synthesis of mesothelial cells, which was alleviated by sgp130 or AG490. IL-6 trans-signalling could induce the phosphorylation of STAT3, which is recruited to the cellular nucleus of Met-5A cells. ConclusionThe present study might provide evidence that high glucose upregulates IL-6 synthesis in Met-5A cells, to some extent, depending on its osmolality and that IL-6 trans-signalling could induce VEGF synthesis partly dependent on the JAK/STAT3 pathway. Summary at a Glance This study explores the effect of high glucose and osmolality on VEGF production in mesothelial cells. Under these conditions mesothelial cells produce IL6 which in turn stimulates the production of VEGF via a mechanism that involves signalling via the JAK/STAT3 pathway.
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