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

目的：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，UUO中产生了活性氧(ROS)，由ROS引起的氧化应激导致不可逆的肾脏损伤，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。本研究旨在探讨丙氨酸对尿路梗阻大鼠肾脏损伤介质转化生长因子-β-1和肾损伤参数的影响。方法：两组SD大鼠均建立左侧UUO模型。第1组：对照组(10例)，于UUO前1天开始口服0.5%羧甲基纤维素钠，并持续至整个研究过程。第2组：ALA治疗(…时口服ALA在UUO前1天开始并在整个研究过程中持续使用0.5%以上的羧甲基纤维素，n=10)。UUO后第14天取肾脏。观察指标：间质纤维化、MASSON三色染色切片点数、成纤维细胞特异性蛋白免疫染色、巨噬细胞浸润、ED-1免疫染色、细胞凋亡、单链DNA免疫染色、转化生长因子-β-1、酶联免疫吸附试验。结果：ALA组梗阻肾间质纤维化程度明显低于对照组(见表)。ALA组肾组织转化生长因子-β水平明显低于对照组(见表)，提示肾组织转化生长因子-β水平下降是ALA治疗改善肾损伤的原因之一。ALA治疗后梗阻肾组织细胞凋亡率明显减少。而对照组和ALA组的巨噬细胞数差异无统计学意义。结论：抗氧化剂α-硫辛酸可降低输尿管梗阻大鼠肾组织转化生长因子-β，改善肾小管细胞凋亡和肾纤维化，但不影响巨噬细胞的浸润。α-硫辛酸可能是一种治疗UUO的临床有用药物。较少

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