【作者】 戎殳；

【导师】 梅长林； 叶朝阳； 赵学智；

【作者基本信息】 第二军医大学 ， 内科学， 2007， 博士

【摘要】 常染色体显性多囊肾病(autosomal dominant polycystic kidney disease, ADPKD)是人类最常见、危害最大的单基因遗传病之一,在世界范围的发病率为1/400~1/1000,我国目前约有150多万人罹患此病,其中50%患者在60岁时会进展至终末期肾衰竭。但是目前对于该病发病机制及病理生理尚不明了,从而导致治疗方面也无重大突破。因此ADPKD及其并发症的发生、发展仍然是今后工作的重点。心血管并发症是ADPKD最早发生、最常见的并发症之一,也是其主要死因之一。囊肿扩张和局部肾缺血导致的肾素-血管紧张素-醛固酮系统(RAAS)激活对ADPKD患者动脉粥样硬化、高血压等心血管病发生及肾衰竭进展起重要作用。RAAS在靶器官损害如动脉粥样硬化、左室肥厚、心力衰竭及肾衰竭中起一定作用。RAAS激活开始于疾病早期阶段,故在主要临床表现出现之前即可发生血管损害,如能早期发现、早期干预,则有利于延缓其心血管并发症的进程。流行病学和临床研究显示动脉损伤是心血管疾病发病和死亡的重要影响因素,其主要的改变包括内皮功能不良、内中膜厚度(IMT)增加及僵硬度增加等。本研究的目的主要在于观察ADPKD动物模型和患者动脉血管病变,为早期评价ADPKD心血管病危险因素提供依据。本研究由两部分组成:1.观察ADPKD模型Han:SPRD大鼠不同表现型不同周龄的血管内皮损伤病理改变,选取4、8、12周龄雄性及雌性SPRD杂合子(Cy/+)和正常(+/+)大鼠各5只,共45只作为研究对象,取降主动脉进行苏木精-伊红染色观察病理形态学变化;免疫组化染色观察细胞间黏附分子-1(ICAM-1)的表达分布。处死动物前测定血压和肾功能。结果发现,光镜下,4周龄大鼠各组均未见明显改变,但8周龄和12周龄雄性Han:SPRD大鼠出现明显的内皮损伤表现,如内皮肿胀、鞋钉样及内皮细胞脱落等,并且12周龄大鼠表现更重。进一步行免疫组织化学检测显示,各周龄雄性SPRD杂合子大鼠内皮细胞表达ICAM-1均增加,由于ICAM-1是内皮细胞损伤的早期标志,故提示内皮细胞功能受损。并且内皮损伤程度与病变严重程度有一定关联,随着血管内皮功能损伤的逐渐加重,雄性SPRD杂合子大鼠肾功能损伤和高血压逐步进展,而病变程度较轻的雌性SPRD杂合子大鼠内皮损伤不明显。不仅如此,早期4周龄的雄性SPRD杂合子大鼠在肾功能尚未出现明显异常及血压尚未显著升高及光镜下未见到显著形态学改变时,即已存在血管内皮功能异常,主动脉内皮细胞ICAM-1表达强度和范围明显增加,显著高于同周龄的雌性SPRD杂合子大鼠和正常大鼠。2.应用高频超声分别探测ADPKD高血压、ADPKD正常血压、原发性高血压及正常对照4组人群的肱动脉内皮依赖性舒张功能、颈动脉内中膜厚度(IMT)及颈动脉扩张性。结果发现①反应性充血后肱动脉内径变化ADPKD高血压组显著小于原发性高血压组和ADPKD正常血压组,并且ADPKD正常血压组显著小于正常对照;②ADPKD高血压组和原发性高血压组IMT均显著高于ADPKD正常血压组和正常对照;并且ADPKD正常血压组IMT也显著高于正常对照;③横断面扩张性(CD)和弹性模量增值(Einc)ADPKD高血压组和原发性高血压组与ADPKD正常血压组和正常对照有显著差异,并且ADPKD正常血压组与正常对照也有显著差异。以上研究结果表明:Han:SPRD大鼠存在内皮功能损伤,该病变可能在ADPKD早期肾功能及血压正常时即已发生。肾功能正常的ADPKD高血压和正常血压患者存在显著的内皮功能受损、IMT增加和颈动脉扩张性降低,提示疾病早期即可能发生动脉损伤。因此,在疾病早期,监测动脉血管功能、采取有效措施延缓动脉损伤的发生、控制其进展对于有效预防ADPKD心血管疾病具有十分重要的意义。更多还原

【Abstract】 Autosomal dominant polycystic kidney disease(ADPKD) is one of the most common human hereditary kidney diseases with a prevalence of 1/400-1/1000, estimated to affect more than 1.5 million people and account for about 5% of end stage renal disease patients requiring renal replacement therapy in China. The disease is characterized by the progressive formation of multiple renal cysts affecting all segments of the renal tubules and about 50% patients develop renal insufficiency in the fifth and sixth decades of life. However, at present the unclearness of pathogenesis and pathophysiology of ADPKD results in no effective treatment to this disease. Therefore, the development of ADPKD and its complications remains the focus.Cardiovascular diseases are one of the earlier and more common complications of ADPKD, and also one of its main causes of death. Renin-angiotensin-aldosterone system (RAAS) plays a role in target organ injuries such as atherosclerosis, left ventricular hypertrophy, heart failure and renal failure. RAAS activation starts at early stage of ADPKD, so arteries injury may occur before clinical menifestation appearance. Early diagnosis and intervention may be benefit to postpone the development of cardiovascular complications.The purpose of our research is observing the arterial changes in animal model and patients of ADPKD, in order to offerring evidence to assess the risk factor of cardiovascular disease in ADPKD.This study consists of 2 sections:1. We observed the pathology of thoracic aorta in Han:SPRD rat with difference phenotype and age. The subject included 45 male heterozygous, female heterozygous (Cy / +) and normal (+ / +) SPRD rats ( 4, 8, 12 weeks old). The blood pressure and renal function were measured, and then the rats were killed , descending aorta was obmined to observe the pathomorphological changes with haematine-eosin staining , and the distribution of the expression of intercellular adhesion molecule-1(ICAM-1) was observed with immunohistochemical staining.It was found that there were distinct changes in male heterozygous rats of 8 and 12 weeks old under light microscope, and the expression of ICAM-1 increased in endothelial cell of male heterozygous rats. The extent of damage in endothelium related to severity of disease. With the aggravation of endothelium injury, the renal function damage and hypertension gradually developed. whereas the endothelial injury in female rats whose diseases were not serious. Moreover, the expression of ICAM-1 in 4-week-old male rats increased significantly when its renal function and blood pressure still remained normal.2. We observed the morphologic, mechanical and functional sonographic parameters of arteties in ADPKD patients with normal renal function. Thirty-two hypertensive and 28 normotensive patients with ADPKD with preserved renal function, 25 patients with essential hypertension, and 30 healthy subjects were included in the study. By means of high-resolution vascular ultrasound, brachial artery endothelial dependent vasodilation (EDV), carotid intima-media thickness (IMT) and distensibility were measured. It is founded that EDV was significant worse in hypertensive patients with ADPKD compared with patients with essential hypertension and normotensive patients with ADPKD, and even in normotensive patients with ADPKD compared with healthy subjects. Carotid IMT was significant greater in both hypertensive and normotensive patients with ADPKD compared with healthy subjects. Moreover, carotid cross-sectional distensibility (CD) and incremental elastic modulus (Einc) differed significantly between both hypertensive and normotensive patients with ADPKD and healthy subjects.It proved that The endothelium injury of Han:SPRD rat might occurred when renal function and blood pressure were nomal. Both hypertensive and normotensive patients with ADPKD show significant endothelial dysfunction, increased IMT and decreased distensibility, which are predictors of artery injury The endothelium injury might occurred when renal function and blood pressure were nomal. Therefore, it is important for prevention cardiovascular disease in ADPKD to monitor arterial function and control it development and advancement.更多还原