https://scholars.lib.ntu.edu.tw/handle/123456789/188345
標題: | Pentoxifylline抑制白蛋白刺激近端腎小管monocyte chemoattractant protein-1表現的機轉 | 作者: | 林水龍 | 關鍵字: | 白蛋白;單核球細胞化學吸引蛋白質-1;pentoxifylline;近端腎小管細胞;Albumin;Monocyte chemoattractant protein-1;renal proximal tubular cells | 公開日期: | 2004 | 出版社: | 臺北市:國立臺灣大學醫學院內科 | 摘要: | 目前已知腎臟間質病變與蛋白尿的多寡是慢性腎病惡化的重要指標,而且 尿液中的蛋白質已被證實可以引起間質發炎,進而引起腎病的繼續惡化。單核球 細胞化學吸引蛋白質-1 【Monocyte chemoattractant protein-1 (MCP-1)】是目前已 知最強的單核發炎細胞化學吸引蛋白質。動物實驗發現MCP-1 會在許多慢性腎 炎的腎臟大量表現,而且阻斷MCP-1 的作用可以改善腎臟病的惡化。白蛋白是 尿蛋白中的主成分,在近端腎小管細胞培養的實驗中發現白蛋白可以刺激MCP-1 分泌,而降低慢性腎病鼠尿蛋白的治療則可以減少腎臟內MCP-1 的表現。過去 吾人已發現pentoxifylline (PTX)可以改善實驗鼠的急性腎炎及慢性腎衰竭。PTX 能夠改善腎病的原因之一可能與其能降低炎性反應有關。事實上,吾人已發現 PTX 能夠減少腎臟內的單核發炎細胞浸潤,以及減少MCP-1 的表現;更有趣的 是在近端腎小管細胞培養的實驗中,PTX 也可以降低白蛋白所刺激的MCP-1 基 因表現。然而PTX 是透過何種機制來降低白蛋白刺激MCP-1 表現則是未知。本 研究探討PTX 抑制白蛋白刺激近端腎小管MCP-1 表現的機轉。吾人將NF-κ B 、 AP1 、及SP1 等binding site 分別進行mutation ,吾人發現AP1B 及SP1 會影響 MCP-1 的basal transcription ,而且NF-κ B 、AP1B 、SP1 與白蛋白刺激近端腎小 管MCP-1 gene 表現有關。吾人正進行EMSA 以了解PTX 是否透過抑制NF-κ B 、 AP1B 、或SP1 等轉錄因子的活化來抑制白蛋白刺激MCP-1 基因的表現。 Interstitial inflammation and proteinuria are hallmarks of progressive chronic renal disease, and proteinuria has been implicated as an effector of progressive renal scarring, particularly through induction of interstitial inflammation. Increasing concentrations of albumin in cultured proximal tubular cells has been shown to upregulate the expression of monocyte chemoattractant protein-1 (MCP-1), one of the most powerful mononuclear cell attractants characterized so far. In our previous studies, pentoxifylline (PTX) has been shown to attenuate experimental mesangial proliferative glomerulonephritis and progressive chronic renal disease. One of the possible mechanisms for the renoprotection may be linked to the effect of PTX against inflammation. Indeed, we have shown that PTX attenuates mononuclear cell infiltration possibly through MCP-1 downregulation in renal cortex as well as in albumin-stimulated proximal tubular cells. However, the detail mechanism by which PTX inhibits MCP-1 induction in albumin-stimulated proximal tubular cells is not known. In promoter activity assay, we found that the basal activity of MCP-1 promoter was reduced after AP1B, or SP1 binding site mutation. Furthermore, the increased promoter activity of MCP-1 by human serum albumin was suppressed in HK2 cells transfected with NF-κ B, AP1B, or SP1 mutated construct. We will further demonstate the target molecule of PTX in suppressing the albumin-induced MCP-1 gene expression. We will also study whether PTX affects the albumin-activated signal pathways involving the activation of AP1 and SP1 binding. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/23648 | 其他識別: | 922314B002193 | Rights: | 國立臺灣大學醫學院內科 |
顯示於: | 醫學系 |
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922314B002193.pdf | 98.08 kB | Adobe PDF | 檢視/開啟 |
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