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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

前言和目的：本研究旨在探讨α-硫辛酸（ALA）对单侧输尿管梗阻（UUO）所致肾损伤的影响。据报道，活性氧（ROS）在UUO中产生，由ROS引起的氧化应激导致不可逆的肾损伤，包括间质纤维化和肾小管细胞凋亡。因此，降低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，其肾脏保护作用已在几种肾脏疾病模型中显示，如肾小球肾炎和糖尿病肾病。本研究旨在观察ALA对UUO大鼠肾损伤介质TGF-β1及肾损伤指标的影响。方法：采用SD大鼠左侧单侧输尿管梗阻模型。第1组：对照组（在UUO前1天开始口服0.5%羧甲基纤维素，并在整个研究期间持续，n=10）。第2组：ALA治疗（在24小时内口服施用ALA）。 ...更多信息 0.5%羧甲基纤维素，在UUO前1天开始，并在整个研究期间持续，n=10）。在UUO后第14天收获肾脏。审查了以下内容：间质纤维化，Masson三色染色玻片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，艾德-1免疫染色;细胞凋亡，ssDNA免疫染色; TGF-β1，ELISA。结果：与对照组相比，ALA组阻塞肾间质纤维化显著减少（见表）。ALA组的组织TGF-β水平显著低于对照组（见表），表明肾脏中TGF-β水平的下降是ALA治疗改善肾损伤的原因之一。ALA能明显减少梗阻肾的凋亡细胞。而对照组和ALA组的巨噬细胞浸润数无显著性差异。结论：抗氧化剂α-硫辛酸可降低组织TGF-β，改善肾小管细胞凋亡和肾纤维化，但对UUO中的巨噬细胞浸润无影响。α-硫辛酸可能是一种临床上有用的治疗UUO的药物。少