LDR与FGF21联用对2型糖尿病肾脏保护作用研究

发布时间：2018-08-16 17:47

【摘要】：糖尿病（diabetes mellitus，DM）是一组以高血糖为特征的代谢性疾病，已成为威胁人类生命健康的三大危险性疾病之一。糖尿病肾病是最常见、最严重的糖尿病微血管并发症之一，最终导致进行性肾功能衰竭，占终末期肾脏疾病新发病例的40%。在我国，，糖尿病肾病已经成为导致终末期肾脏疾病的第二位病因，并且其发病率均呈现一个快速增长的趋势，给人们生活带来极大的负担。2型糖尿病占所有确诊糖尿病患者的90%以上，因此，如何预防和治疗2型糖尿病肾病已经成为医学界急需解决的问题。目前认为，糖、脂代谢紊乱及其诱导的氧化应激是导致2型糖尿病肾病关键诱因。与高剂量电离辐射不同，LDR诱导机体适应性反应，提高机体抗氧化功能，降低炎症反应。另外，FGF21作为一个新型药物在治疗2型糖尿病及相关代谢紊乱疾病上表现出希望。临床试验证实，FGF21可持续控制血糖和血脂，改善胰岛素抵抗，提高β-细胞功能，同时很少出现常见治疗药物的副作用如低血糖、水肿以及肥胖。本实验引入LDR及FGF21两个关键干预因素，分别对辐射与FGF21剂量及干预时程进行优化之后实现联合作用，用以探讨两者联用对于糖尿病肾病的预防或治疗的协同作用。本研究采用的实验方法，包括Western-blot、qRT-PCR、IHC以及ELISA等，从基因、蛋白质和组织水平研究LDR（25mGy、50mGy和75mGy）和FGF21（0.5mg/kg、1.5mg/kg和2.5mg/kg）分别处理4周和8周之后，对糖尿病小鼠的外周血生物化学指标及肾脏组织的不同抗氧化因子（Nrf-2、HO-1、NQO-1、SOD-1）和炎症因子（ICAM-1、TNF-α和PAI-1）的影响，进而选择二者最佳治疗方式，探讨将其联用后对2型糖尿病肾病的保护作用及其机制。结果显示，LDR和FGF21单一处理均能有效延缓2型糖尿病肾脏疾病的进程；相比单一处理，二者联合作用进一步抑制2型糖尿病诱导的肾脏损伤。本研究结果提示，LDR与FGF21联合作用可有效阻止2型糖尿病肾病的发展，改善糖尿病小鼠的肾脏功能，对糖尿病肾病有明显的保护作用，其机制可能与机体血糖降低、改善血脂代谢谱以及抗氧化功能升高有关，但仍需进一步深入探讨。
[Abstract]:Diabetes mellitus (diabetes mellitus DM) is a metabolic disease characterized by hyperglycemia, which has become one of the three dangerous diseases threatening human life and health. Diabetic nephropathy is one of the most common and severe diabetic microvascular complications, leading to progressive renal failure, accounting for 40 new cases of end-stage renal disease. In China, diabetic nephropathy has become the second leading cause of end-stage renal disease, and the incidence of diabetic nephropathy has shown a rapid growth trend. Type 2 diabetes accounts for more than 90% of all diagnosed diabetic patients. Therefore, how to prevent and treat type 2 diabetic nephropathy has become an urgent problem in the medical field. It is believed that the disorder of glucose and lipid metabolism and oxidative stress are the key factors leading to type 2 diabetic nephropathy. Different from high dose of ionizing radiation, LDR induces adaptive response, improves antioxidant function and reduces inflammatory response. In addition, FGF21 as a new drug in the treatment of type 2 diabetes mellitus and related metabolic disorders show hope. Clinical trials have proved that FGF21 can sustainably control blood glucose and lipids, improve insulin resistance, and improve 尾 -cell function, while side effects of common therapeutic drugs such as hypoglycemia, edema and obesity are rare. In this experiment, two key intervention factors, LDR and FGF21, were introduced to optimize the dose of radiation and FGF21 and the duration of intervention, respectively, to achieve the combined effect, so as to explore the synergistic effect of the two combined therapy on the prevention or treatment of diabetic nephropathy. The experimental methods used in this study, including Western-blottqRT-PCRHC and ELISA, were used to study the effects of LDR (25mGy, 50mGy and 75mGy) and FGF21 (0.5mgr / kg 1.5mg / kg and 2.5mg/kg) on gene, protein and tissue levels for 4 and 8 weeks, respectively. The effects of different antioxidant factors (Nrf-2HO-1, NQO-1SOD-1) and inflammatory factors (ICAM-1, TNF- 伪 and PAI-1) on peripheral blood biochemical indexes and renal tissue of diabetic mice were studied. To investigate the protective effect and mechanism of combined therapy on type 2 diabetic nephropathy. The results showed that both LDR and FGF21 single treatment could effectively delay the progression of renal disease in type 2 diabetes mellitus, and the combination of them could further inhibit the renal injury induced by type 2 diabetes mellitus. The results suggest that the combination of LDR and FGF21 can effectively prevent the development of type 2 diabetic nephropathy, improve the renal function of diabetic mice, and have an obvious protective effect on diabetic nephropathy, and its mechanism may be related to the decrease of blood glucose. The improvement of lipid metabolism spectrum and the increase of antioxidant function are related, but need to be further discussed.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R587.2;R692

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