Development of nobel pharmacological treatment to inhibit renal fibrosis caused by unilateral ureteral obstruction

开发抑制单侧输尿管梗阻引起的肾纤维化的诺贝尔药物治疗方法

基本信息

批准号：
22590257
负责人：
ITO Keiichi
金额：
$ 2.83万
依托单位：
National Defense Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

Introduction and Objective: We focused on the effect of alpha-lipoic acid (ALA) on renal injury caused by unilateral ureteral obstruction (UUO). Reactive oxygen species (ROS) is reportedly generated in UUO and oxidative stress caused by ROS results in irreversible renal damage including interstitial fibrosis and tubular apoptosis. Thus agents that decrease oxidative stress are potential effective tools for the treatment of UUO. ALA is an antioxidant and its renoprotective effects have been shown in several renal disease models such as glomeronephritis and diabetic nephropathy. The present study was undertaken to evaluate the effects of ALA on mediator of renal injury, TGF-β1, and parameters of renal injury in a rat UUO model. Methods: Two groups of Sprague-Dawley rats were subject to left UUO. Group 1: control (oral administration of 0.5% carboxylmethyl cellulose beginning 1 days prior to UUO and continuing throughout study, n=10). Group 2: ALA treatment (oral administration of ALA in … More 0.5% carboxylmethyl cellulose beginning 1 days prior to UUO and continuing throughout study, n=10). Kidneys were harvested at day 14 after UUO. The following was examined: interstitial fibrosis, point counting of Masson's trichrome-stained slides and fibroblast specific protein (FSP) immunostaining; macrophage infiltration, ED-1 immunostaining; apoptosis, ssDNA immunostaining; TGF-β1, ELISA. Results: Interstitial fibrosis in obstructed kidney was significantly decreased in ALA group compared to control group (See table). Tissue TGF-β levels were significantly lower in ALA group compared to control group (See table), suggesting that the decline in TGF-β level in the kidney was one of causes for the improvement of renal injury by ALA treatment. Apoptotic cells in obstructed kidney were significantly decreased by ALA treatment. In contrast, there was no significant difference in the number of infiltrated macrophage between control and ALA group. Conclusions: Antioxidant, α-lipoic acid, decreases tissue TGF-β and improved tubular apoptosis and renal fibrosis but not macrophage infiltration in UUO. Alfa-lipoic acid may be a clinically useful agent for the treatment of UUO. Less

简介和目的：我们重点研究α-硫辛酸（ALA）对单侧输尿管梗阻（UUO）引起的肾损伤的影响据报道，UUO 中会产生活性氧（ROS），ROS 引起的氧化应激会导致不可逆的肾损伤。因此，减少氧化应激的药物是治疗 UUO 的潜在有效工具，ALA 是一种抗氧化剂，具有肾脏保护作用。本研究旨在评估 ALA 对大鼠 UUO 模型中肾损伤介质 TGF-β1 和肾损伤参数的影响。的 Sprague-Dawley 大鼠接受左侧 UUO 组：对照（在 UUO 前 1 天开始口服 0.5% 羧甲基纤维素）。第 2 组：ALA 治疗（在 UUO 前 1 天开始口服含 0.5% 羧甲基纤维素的 ALA，并在 UUO 后第 14 天继续进行研究，n=10）。检查以下内容：间质纤维化、Masson三色染色玻片的点计数和成纤维细胞特异性蛋白（FSP）免疫染色；巨噬细胞浸润、ED-1 免疫染色、凋亡、ssDNA 免疫染色、TGF-β1、ELISA 结果：与对照组相比，ALA 组的组织 TGF-β 水平显着降低。 ALA组与对照组比较（见表），提示肾脏内TGF-β水平下降是ALA改善肾损伤的原因之一ALA 治疗后梗阻肾中的凋亡细胞显着减少，而对照组和 ALA 组之间浸润的巨噬细胞数量没有显着差异。结论：抗氧化剂 α-硫辛酸可降低组织 TGF-β，并改善。 α-硫辛酸可能是治疗 UUO 的临床有用药物。