行政院國家科學委員會專題研究計畫 成果報告
併用 Phosphodiesterase inhibitor 及
Angiotensin-converting enzyme inhibitor 對慢性腎病之
療效
計畫類別： 個別型計畫 計畫編號： NSC90-2314-B-002-262- 執行期間： 90 年 08 月 01 日至 92 年 03 月 31 日 執行單位： 國立臺灣大學醫學院內科 計畫主持人： 林水龍 計畫參與人員： 王美琳,楊靜欽 報告類型： 精簡報告 處理方式： 本計畫可公開查詢中 華 民 國 92 年 6 月 16 日
中文摘要
關鍵詞：pentoxifylline,腎臟六分之五亞全切除, cilazapril 吾人先前的研究已經證實 pentoxifylline，一種臨床上常用的 phosphodiesterase 抑制劑，可以改善實驗性的腎膈細胞增生性腎絲球腎炎。本研 究的假設是 pentoxifylline 也能有效地延緩慢性腎病惡化。接受腎臟六分之五亞 全切除的鼠會產生漸進惡化的蛋白尿、氮血症、腎絲球硬化、腎間質發炎、與纖 維化，而 pentoxifylline 的治療可以改善以上慢性腎病的表現約 40 到 60%。然而， pentoxifylline 並無法改善高血壓。Pentoxifylline 可以降低殘餘腎內皮質部增加的 單核球化學吸引蛋白質-1 基因約 60%，而且白蛋白或第二型血管張力素刺激近 端腎小管上皮細胞所產生的單核球化學吸引蛋白質-1 基因也可以被 pentoxifylline 抑制下來。除了皮質部單核球化學吸引蛋白質-1 基因受到 pentoxifylline 抑制之外，血小板衍生的生長因子、第二型纖維母細胞生長因子、 1 轉化生長因子、結締組織生長因子、以及第一和第三膠元蛋白等增加表現的 基因也都會因 pentoxifylline 的治療而降低。而 pentoxifylline 也可以減少 60%腎 臟間質纖維母細胞的浸潤及抑制培養的纖維母細胞的生長。第二型血管張力素及 1 轉化生長因子可以刺激纖維母細胞與腎膈細胞的結締組織生長因子基因表 現，然而此增加的基因表現也可被 pentoxifylline 抑制下來。吾人進一步合併使 用 pentoxifylline 與血管張力素轉化脢抑制劑 cilazapril 來治療鼠的慢性腎病，結 果發現此合併治療幾乎可以完全阻止慢性腎病的惡化。總結來說，單獨以 pentoxifylline 治療可以有效地減緩鼠的慢性腎病惡化；而合併 pentoxifylline 與 cilazapril 的治療則幾乎可以完全阻止腎病惡化。英文摘要
Key words: pentoxifylline, subtotal nephrectomy, cilazapril
We previously reported that pentoxifylline, a phosphodiesterase inhibitor, attenuates experimental mesangial proliferative glomerulonephritis. In this study, we hypothesized that pentoxifylline could also attenuate the renal disease progression in rats with remnant kidney. After 5/6 subtotal nephrectomy, rats developed
progressively elevated proteinuria and plasma creatinine, glomerulosclerosis, interstitial inflammation and fibrosis, all of which were attenuated by 40 to 60% by pentoxifylline. However, the elevated blood pressure was not changed by
pentoxifylline. Pentoxifylline reduced the upregulation of monocyte chemoattractant protein-1 gene by 60% in the cortex of remnant kidney, as well as in a dose-dependent manner in the albumin- or angiotensin II-stimulated proximal tubular cells. It also reduced the upregulation of mitogenic and profibrogenic genes by 50%, including platelet-derived growth factor, fibroblast growth factor-2, transforming growth factor-1, connective tissue growth factor, types I and III collagen in the cortex of remnant kidney. Furthermore, pentoxifylline was found to decrease the numbers of interstitial myofibroblasts by 60% in the cortex of remnant kidney and suppress the proliferation of cultured interstitial fibroblasts. It also reduced the angiotensin II- or transforming growth factor-1-induced expression of connective tissue growth factor gene in cultured fibroblasts and mesangial cells. Combining pentoxifylline with an angiotensin-converting enzyme inhibitor, cilazapril, almost completely attenuated the renal disease progression in rats with remnant kidney. In conclusion, pentoxifylline alone can attenuate the chronic renal disease progression. Its combination with cilazapril has the potential to prevent the renal disease progression almost completely.
