第四章、 討論
第二節 其他相關性討論
第二節 其他相關性討論
輸尿管阻塞後會引起單核細胞／巨噬細胞在腎臟的浸潤。腎小管 間質被發炎細胞的浸潤在很多種的慢性腎臟病都已被發現。在腎臟持 續的發炎反應被認為和腎小管間質纖維化及腎功能惡化有相關性
87。巨噬細胞經由釋放活性氧化物質(Reactive oxygen species; ROS)、
一氧化氮(nitric oxide; NO)、補體(complement)和前發炎細胞激素 (proinflammatory cytokines)所造成的組織傷害己經有文獻報告88。我 們的實驗顯示單核細胞／巨噬細胞的浸潤在阻塞的腎臟可被 DRI 有
31 裂活化蛋白質激酶(MAPK)、ERK 1/2 及 PI3K-p85。活化 MAPK、ERK 1/2 及 PI3K-p85 可能會有前纖維化（profibrotic）及增殖(proliferation) 的效果，最後造成器官的損傷，稱為第二血管張力素獨立路徑
（Angiotesin II-independent pathway）。而經由增加腎素催化活性也會 經由第二血管張力素的作用造成器官的損傷，稱為第二血管張力素依 賴路徑（Angiotesin II-dependent pathway）。最近有學者提出腎素或 前腎素和（前）腎素受體結合後會活化PLZF 蛋白(Promyelocytic zinc-finger protein)86。PLZF 蛋白進入細胞核後會負回饋去抑制（前）
腎素受體的轉錄（transcription），同時會活化 PI3K-p85α的轉錄 91。 PI3K-p85α可能藉由 Akt kinase 再進一步活化 MAPK 及 ERK 1/292。 Aliskiren 無法抑制（前）腎素受體，因此若能找一個藥物能阻斷（前）
腎素受體同時也能抑制腎素催化血管張力素原，則將能在抑制腎纖維 化，增進心臟血管的保護作用及控制血壓有最佳的療效。
32
第三節 研究限制
在我們的研究仍有一些限制。我們並沒有評估在 UUO 後的大鼠 的血壓和白蛋白尿。高血壓和白蛋白尿在糖尿病的病人很常見並且是 慢性腎疾病和腎纖維化的重要的危險因子。然而，aliskiren 在糖尿病 腎病變的老鼠模式已證實可降低白蛋白尿和腎絲球硬化並且和血壓 無關42。另一方面， UUO 後的大鼠仍有一側腎臟是正常的，因此短 時間不會有高血壓及蛋白尿的問題，且先前的研究已發現使用 RAS 抑制劑在UUO 後的大鼠，對血壓及白蛋白尿影響很小。
33
第五章、結論與建議 第一節 結論
總括而言，我們的發現提供了一個活體內(in vivo)的證據證明 aliskiren、 valsartan 或合併治療在大鼠 UUO 引發的腎纖維化的模式 可以減緩腎小管間質的傷害。這樣的結果強烈建議合併 DRI 及 ARB 的治療來改善慢腎性腎病變需要進一步的臨床評估。
第二節 建議
將來計畫進行合併 DRI 及 ARB 的治療來改善慢腎性腎病變臨床 試驗。若能如同動物實驗一般在抑制腎臟纖維化有加成的效果，將使 慢性腎臟病的治療更為有效。
另一方面，（前）腎素受體在此 UUO 引發的腎纖維化的模式 所扮演的角色，以及使用aliskiren 和 valsartan 的合併治療所造成腎 素增加對腎臟纖維化的影響跟（前）腎素受體之間的關係為何，都是 值得我們進一步探討的課題。
34
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附圖:
圖1、腎素-血管張力素-醛固酮系統。(a) 全盤的概述不同種的藥物如 何作用於此系統。ACE， angiotensin-converting enzyme，血管張力素 轉化酶； AT1R， angiotensin II type 1 receptors，第二血管張力素第 一型受體; MR， mineralocorticoid receptor，鹽皮質激素受體。 (b) 阻 斷腎素-血管張力素-醛固酮系統的藥物種類及其對於RAAS系統的 影。 因為回饋機制及替代路徑，抑制某一層級的RAAS 會導致另一 個層級的活化。資料來源：Slagman, et al. Current Opinion in
Nephrology and Hypertension 2010, 19:140–152
45
46
圖
2、Aliskiren 分子結構式。Aliskiren 是第一個口服的腎素直接抑制
劑，它的分子量是609.8，可經由作用於腎素的活性位置來阻斷腎素 的活性。47
圖
3、阻斷 RAS 在 UUO 後 7 天及 14 天可改善因 UUO 所造成的阻
塞腎臟的長度及重量。*代表 P 值小於 0.05 (與同天數接受 UUO 手術 但未餵食藥物的大鼠比較)；**代表 P 值小於 0.005(與同天數接受 UUO 手術但未餵食藥物的大鼠比較)。+代表 P 值小於 0.05(與同天數接受 UUO 手術又餵食 valsartan 或 aliskiren 的大鼠比較)；++代表 P 值小於圖