Signal Transduction Mechanisms of High Glucose-induced Monocyte Chemoattractant Protein-1 Expression in Renal Interstitial Fibroblasts
Date Issued
2006
Date
2006
Author(s)
Hung, Chung-Ying
DOI
zh-TW
Abstract
Background. Diabetic nephropathy is a major complication of diabetes and the single most common disorder leading to end stage renal disease (ESRD). In diabetic nephropathy the prognosis worsens significantly if interstitial inflammation that leads to interstitial fibrosis develops. Monocyte chemoattractant protein-1 (MCP-1) is a CC chemokine well known for its ability in promoting the migration of monocytes. Locally produced MCP-1 is involved in the development of advanced diabetic nephropathy, especially in the formation of tubulointerstitial lesions. Moreover, renal interstitial fibroblasts have been implicated in the development of interstitial fibrosis. However, it is not clear whether renal fibroblasts play a role in renal inflammation in diabetic nephropathy. In this study we hypothesized that renal interstitial fibroblasts and MCP-1 participate in the inflammatory responses of diabetic nephropathy. We thereby investigated the effects of high glucose on the expression of MCP-1 by renal interstitial fibroblasts, and examined the signal transduction mechanisms whereby high glucose acts to affect MCP-1 production.
Methods. NRK-49F cells (rat kidney interstitial fibroblast) were incubated with glucose (5.6 to 35 mmol/L) for up to five days. The MCP-1 concentration in the conditioned media was determined by Western blot analysis and the MCP-1 mRNA expression was examined using Northern blot analysis. To investigate the role of nuclear factor-kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) in high glucose induced MCP-1 expression, NRK-49F cells were treated with NF-kappa B inhibitor MG132, extracellular signal-regulated kinases（ERK）1/2 inhibitor PD98059, c-Jun amino-terminal kinases（JNK）inhibitor SP600125, or p38 MAPK inhibitor SB203580 before high glucose treatment.
Result. Incubation of NRK-49F with high glucose (35 mM) resulted in a time-dependent increase in MCP-1 mRNA expression and protein secretion. Coincubation of the cells with high glucose and MG132 blunted high glucose-mediated MCP-1 mRNA expression. PD98059, SP600125 and SB203580 also attenuated high glucose induced MCP-1 mRNA expression.
Conclusion. These results suggest that high glucose induces MCP-1 synthesis in kidney interstitial fibroblasts by ERK 1/2, p38 MAPK, JNK-c-Jun/AP-1 and NF-kappa B signaling pathways.
Subjects
腎間質纖維母細胞
第一型單核球趨化蛋白質
訊息傳遞
High glucose
Renal interstitial fibroblasts
Monocyte chemoattractant protein-1
Signal transduction
SDGs
Type
text
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