探討牡丹酚衍生物 3I、3J 對 streptozotocin 誘導糖尿病腎病變小鼠之影響

Abstract

糖尿病是造成末期腎臟衰竭的主要原因。雖然大多數的患者可以透過嚴格血糖控制，來降低腎臟病變風險與減緩糖腎病的病程發展，然而仍有許多患者因血糖管理較差進而引起相關併發症，因此研發能夠預防糖尿病腎病變的藥物對於病患是極為重要的事。糖尿病病患體內高血糖環境會引起血管內皮細胞發炎反應，刺激血管平滑肌增生進而促使動脈粥狀硬化。 根據實驗結果，牡丹酚衍生化合物 (Paeonol derivative compounds) 能夠改善血管平滑肌內皮細胞發炎、增生以及抑制活性氧物種（Reactive oxygen species,ROS）產生，此功效也可運用在預防糖尿病造成的腎臟損傷。目前已知血管收縮素轉換酶 2 (Angiotensin converting enzyme2, ACE2) 能夠透過減少血管收縮素II (angiotensin II, Ang II) 生成以及抑制腎素-血管收縮素-醛固酮系統 (Renin Angiotensin-Aldosterone System, RAAS) 藉此預防糖尿病造成的腎臟損傷。此外，ACE2具有將 Ang II 降解成血管緊張素轉換酶 (1-7) 的功能，缺乏 ACE2的小鼠會引發腎臟疾病。因此，本次實驗我們建立了剔除 ACE2基因的小鼠，同時連續五天注射鏈脲佐菌素 (Streptozocin, STZ)，劑量為 50mg/kg，鏈脲佐菌素對於胰臟 β 細胞具有毒性，能誘導生成糖尿病腎病變模型。 由於牡丹酚具有抑制發炎反應與 ROS 產生，我們使用牡丹酚衍生物 3I、3J 來治療糖尿病腎病變的小鼠，根據實驗結果顯示，有注射 3I、3J 的小與控制組相比較尿液 中白蛋白的排泄量明顯降低，另外 3I、3J 具有保護腎臟的功效，能夠減少腎絲球系膜細胞 (Intraglomerular mesangial cells) 增生、發炎反應與纖維化。

Diabetic nephropathy is the leading cause of end-stage Renal Disease worldwide. Although tight control of blood sugar can decrease the risk of diabetic kidney disease, many patients with adequate control develop nephropathy, while others remain complication-free despite poor glycemic control. Thus, it is important to find available drugs or compounds to preventive intervention.

Angiotensin converting enzyme2 (ACE2 ) is known to play an early protective role in the development of diabetic nephropathy through inhibiting renin-angiotensin system (RAS) and the generation of angiotensin (Ang) II. Moreover, ACE2 serves the dual functions of degrading the vasoconstrictor Ang II and producing the vasodilator Ang (1-7). Mice lacking ACE2 have developed kidney disease at 12-month of age. Here, we established the ACE2-/y mice for an early stage of diabetic mellitus. For this propose, we used streptozotocin (50mg/kg), a naturally occurring chemical that is particularly toxic to the insulin-producing beta cells, for 5 days to induce diabetic nephropathy in ACE2-/y mice.

Furthermore, paeonol has been known to inhibit inflammation, cells proliferation rate and ROS. In this study, we used paeonol derivatives compounds (3I and3J) to treat ACE2-/y diabetic mice for one month, and found that compounds 3 I and 3 J reduced urinary albumin excretion compared to ACE2-/y diabetic mice without injecting 3I and 3J. In addition, after treating compounds 3 I and 3 J, we observed that reduction of mesangial expansion, inhibition of inflammation, and decrease of renal fibrosis. Therefore, our studies show that compounds 3 I and 3 J can significantly intervene the development of diabetic.