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海带低分子量褐藻多糖硫酸酯对糖尿病肾病的治疗作用及机制研究
徐颖婕
学位类型博士
导师段德麟 ; 张全斌
2016-05-25
学位授予单位中国科学院大学
学位授予地点北京
学位专业海洋生物学
关键词褐藻多糖硫酸酯 糖尿病肾病 P-选择素 乙酰肝素酶 炎症应答 肾小球
摘要糖尿病肾病(DN)是糖尿病严重的微血管并发症之一,是慢性肾衰和终末期肾病的主要诱因之一,是导致糖尿病患者死亡的主要原因。DN作为糖尿病引起的代谢障碍并发症,其发生发展与多种病理过程有关。寻找治疗DN的有效药物,改善患者的生存质量迫在眉睫。
低分子量褐藻多糖硫酸酯(LMWF)是从海带中制备的主要由岩藻糖和半乳糖组成的高度硫酸化的杂多糖。LMWF具有多种生物活性,包括抗凝血、抗炎症、抗血管生成、抗氧化、抗肿瘤和抗病毒等活性。多糖及糖复合物作为生命体的重要组成部分,在糖尿病肾病的发生和发展过程中起着重要作用。LMWF作为天然海藻硫酸多糖,很有可能通过对糖尿病肾病发生关键过程中的糖复合物的功能进行干预,抑制糖尿病肾病的发生和发展。本论文采用链脲佐菌素(STZ)诱导的糖尿病肾病模型,研究LMWF治疗糖尿病肾病的作用及其机制。
⑴  采用STZ诱导糖尿病肾病模型,DN大鼠出现典型的糖尿病肾病症状,尿微量总蛋白(M-TP)和尿白蛋白(uAlb)显著升高。LMWF灌胃给药能够阻止大鼠体重和尿量的减少,显著降低血液和尿液中的各项生化指标,减轻DN大鼠尿液中M-TP和uAlb的水平,减少蛋白尿的发生。减轻DN大鼠的肾脏损伤,保护和维持肾小球的基本结构及功能,进而缓解DN的发生发展。
⑵  炎症应答与DN的发生发展密切相关。苏木精-伊红(HE)染色显示LMWF能够保护DN大鼠肾脏正常的生理结构,缓解炎症反应和炎症细胞浸润水平。LMWF治疗组大鼠体内P-选择素和选择素依赖的炎症细胞因子的阳性表达不论是在转录水平还是蛋白水平都有明显的下调。表明LMWF能够减缓由P-选择素和炎症细胞因子所介导的炎症反应从而保护DN大鼠的肾脏功能。
⑶  肾小球基底膜(GBM)是实现肾小球滤过功能的重要元件,而硫酸乙酰肝素蛋白聚糖(HSPGs)是GBM的重要组成部分。乙酰肝素酶(HPSE)能够降解HSPGs中的硫酸乙酰肝素(HS)侧链,破坏肾小球的正常生理结构及功能。LMWF能够降低DN大鼠体内的糖胺聚糖的含量和晚期糖基化终末产物受体(AGER)的表达水平。LMWF还能够维持GBM和肾小球的结构完整性,进而改善肾小球的滤过功能,防止肾小球内的糖胺聚糖的不正常降解,抑制AGER的产生和累积对肾小球造成的损伤。并且,不论是在转录水平还是蛋白水平,LMWF能够下调HPSE及相关生长因子在DN大鼠体内的阳性表达。因此,本实验结果证实,LMWF能够通过抑制HPSE及相关生长因子的表达,维持肾小球的基本结构和功能,以此来缓解DN的发生发展。
其他摘要Diabetic nephropathy (DN) is a serious and major microvascular complication caused by diabetes, it can lead to chronic renal failure and end-stage renal failure, and it is the major cause of death in diabetic patient. DN is a kind of metabolic disorders caused by diabetes, its onset and development are involved in various pathological processes. It is extremely urgent to look for an effective drug for DN and improve patient quality of life.
Low molecular weight fucoidan (LMWF) is a highly sulfated heteropolysaccharide degraded from fucoidan of Saccharina japonica, it is made up mostly of fucose and galactose. LMWF has a variety of activities on anticoagulant, anti-inflammatory, antiangiogenic, antioxidant, antitumor and antiviral and so on. Polysaccharide and glycoconjugates are important biomacromolecule, they play a key role in the onset and development of DN. LMWF in one of natural sulfated polysaccharides from seaweed, it may affect the function of glycoconjugates which are involved in the onset and development of DN, and inhibit the development of DN. This research aims to explore the mechanism and treatment of LMWF on streptozotocin (STZ)-induced DN model. The main results are as follows:
(1)     STZ were used to induce DN model in rats, and then DN rats had typical DN symptoms, the levels of microscale-total protein (M-TP) and urinary albumin (uAlb) were increased obviously. LMWF could prevent body weight losing and reduction of urine by oral administration, significantly reduced the levels of biochemical indices in blood and urine. LMWF decreased M-TP and uAlb content in urine, then reduced the incidence of proteinuria. In addition, LMWF mitigated the renal damage of DN rats, maintained the basic structure and function of glomerulus, and then alleviated the onset and development of DN.
(2)     It is understood that inflammation is associated with the onset and process of DN. The hematoxylin and eosin (HE) stained sections exhibited LMWF protected normal morphological structures and reduced inflammatory cell infiltration in the kidneys of DN rats. Furthermore, LMWF significantly decreased the levels of P-selectin and selectin-dependent inflammatory cytokines at both transcriptional and protein levels. Thus, our results found that LMWF alleviated inflammation through the modulation of P-selectin and inflammatory cytokines and protected the renal function in DN rats.
(3)     Glomerular basement membrane (GBM) is the necessary component of glomerular filtration function, and HSPGs are the important composition of GBM. Heparanase (HPSE) can cleave the heparan sulfate (HS) chain of HSPGs, lead to the physiological structure and function of glomerulus damaged. Results showed that LMWF could lower hyaluronic acid (HA) levels and advanced glycosylation end product-specific receptor (AGER) levels in DN rats. And LMWF maintained the structural integrity of GBM and glomerulus, improved the glomerular filtration function, protected glycosaminoglycan from abnormal degrading, prevented advanced glycosylation end product (AGE) from being generated and accumulating. Furthermore, LMWF could downregulate the levels of HPSE and growth factors at both the transcriptional and protein levels. Thus, our results found that LMWF inhibited the positive expression of HPSE and growth factors, maintained the normal structure and function of glomerulus, then ameliorated the development of DN.
语种英语
文献类型学位论文
条目标识符http://ir.qdio.ac.cn/handle/337002/116963
专题实验海洋生物学重点实验室
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徐颖婕. 海带低分子量褐藻多糖硫酸酯对糖尿病肾病的治疗作用及机制研究[D]. 北京. 中国科学院大学,2016.
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