细胞外超氧化物歧化酶通过抑制 ROS/ERK1/2 信号通路改善链脲佐菌素诱导的大鼠糖尿病肾病。
Extracellular superoxide dismutase ameliorates streptozotocin-induced rat diabetic nephropathy via inhibiting the ROS/ERK1/2 signaling.
机构信息
Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan; Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung 411, Taiwan; National Defense Medical Center, Taipei 114, Taiwan.
Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
出版信息
Life Sci. 2015 Aug 15;135:77-86. doi: 10.1016/j.lfs.2015.04.018. Epub 2015 May 23.
AIM
Diabetic nephropathy is the leading cause of end stage renal disease in developed countries throughout the world. The imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense system is the main problem that is responsible for the progression of diabetic kidney disease. In this study, we investigated whether human extracellular superoxide dismutase (hEC-SOD) can prevent diabetic nephropathy in the rat model.
MAIN METHODS
Diabetic nephropathy symptoms were induced by intraperitoneal injection with 60 mg/kg streptozotocin (STZ) in male Sprague-Dawley (SD) rats. After daily supplement of rhEC-SOD (3200 U/kg/day) for 4 weeks, the serum or urine biochemical markers (glucose, creatinine, blood urea nitrogen, triglyceride, hemoglobin A1c, and microalbuminuria), histological changes, gene expressions (phox47, opn, and gapdh), and protein levels (TGF-β, AT1-R, phospho-p42/p44 MAPK, and p42/p44 MAPK) were determined.
KEY FINDINGS
Results showed that rhEC-SOD administration could reverse SOD activity measured in kidney and diabetic-associated changes, including the fibrosis change, expression of collagen I, transforming growth factor-beta (TGF-β) and angiotensin II type I receptor (AT1-R), as well as the activation of the intracellular mitogen-activated protein kinase (MAPK) signaling pathway, associating with its inhibition of p42(MAPK)/p44(MAPK) (ERK1/2) phosphorylation. Additionally, diabetic nephropathy up-regulated the expression of the phox47 and opn genes, and these changes could also be suppressed. Though the proteinuria did not significantly reduce. Treatment with rhEC-SOD ameliorates STZ-induced diabetic nephropathy, leading to reduced death rates, kidney weight/body weight ratio, fibrosis change, and TGF-β1 expression through the down-regulation of ROS/ERK1/2 signaling pathway.
SIGNIFICANCE
We conclude that rhEC-SOD can act as a therapeutic agent to protect the progression of diabetic nephropathy.
目的
糖尿病肾病是世界上发达国家终末期肾病的主要原因。活性氧（ROS）产生与抗氧化防御系统之间的失衡是导致糖尿病肾病进展的主要问题。在这项研究中，我们研究了人细胞外超氧化物歧化酶（hEC-SOD）是否可以预防大鼠模型中的糖尿病肾病。
主要方法
雄性 Sprague-Dawley（SD）大鼠腹腔注射 60mg/kg 链脲佐菌素（STZ）诱导糖尿病肾病症状。rhEC-SOD（3200U/kg/天）每天补充 4 周后，测定血清或尿液生化标志物（葡萄糖、肌酐、血尿素氮、甘油三酯、糖化血红蛋白和微量白蛋白尿）、组织学变化、基因表达（phox47、opn 和 gapdh）和蛋白水平（TGF-β、AT1-R、磷酸化 p42/p44 MAPK 和 p42/p44 MAPK）。
主要发现
结果表明，rhEC-SOD 给药可逆转肾脏 SOD 活性和糖尿病相关变化，包括纤维化改变、胶原 I、转化生长因子-β（TGF-β）和血管紧张素 II 型 1 型受体（AT1-R）的表达，以及细胞内有丝分裂原激活的蛋白激酶（MAPK）信号通路的激活，与 p42（MAPK）/p44（MAPK）（ERK1/2）磷酸化的抑制有关。此外，糖尿病肾病上调了 phox47 和 opn 基因的表达，这些变化也可以被抑制。尽管蛋白尿没有显著减少。rhEC-SOD 治疗可改善 STZ 诱导的糖尿病肾病，降低死亡率、肾重/体重比、纤维化改变和 TGF-β1 表达，通过下调 ROS/ERK1/2 信号通路。
意义
我们得出结论，rhEC-SOD 可以作为一种治疗剂，保护糖尿病肾病的进展。
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