發(fā)布時(shí)間：2018-06-18 12:33

  本文選題：特發(fā)性膜性腎病 + 發(fā)病機(jī)制��； 參考：《河北醫(yī)科大學(xué)》2014年碩士論文

【摘要】：目的：膜性腎�。╩embranous nephropathy, MN）是成年人腎病綜合征(nephrotic syndrome, NS)最常見(jiàn)的病理類(lèi)型之一。據(jù)統(tǒng)計(jì)，成年人中約75%的病例主要為特發(fā)性膜性腎病(idiopathic membranous nephropathy,IMN)，而25%的病例則繼發(fā)于各種各樣的原因，包括腫瘤、感染、自身免疫疾病、代謝性疾病以及藥物、毒物損害等。1/4-1/3IMN患者可完全或部分自發(fā)緩解，大量蛋白尿的患者,自發(fā)緩解率可占到20%左右，其余患者會(huì)緩慢進(jìn)展至終末期腎臟病，或在5-16年后死于并發(fā)癥及其他疾病。近年來(lái)，IMN的發(fā)病率呈逐年上升趨勢(shì)，但其具體發(fā)病機(jī)制的研究仍不是很透徹，普遍認(rèn)為是機(jī)體針對(duì)腎臟足細(xì)胞產(chǎn)生特異性IgG4抗體，形成上皮下免疫復(fù)合物而致病。因此明確IMN的發(fā)病機(jī)制有重要意義，將對(duì)疾病的診斷和治療提供新的幫助。 錳超氧化物歧化酶（manganese superoxide dismutase,SOD2）是廣泛的抗氧化細(xì)胞保護(hù)系統(tǒng)的重要組成部分，是一種抗氧化金屬酶，可將毒性的超氧化物陰離子轉(zhuǎn)化為過(guò)氧化氫和雙原子氧，在機(jī)體氧化與抗氧化平衡中起到至關(guān)重要的作用。當(dāng)機(jī)體在遭受各種有害刺激時(shí)，體內(nèi)高活性分子產(chǎn)生過(guò)多，氧化系統(tǒng)和抗氧化系統(tǒng)失衡，使機(jī)體處于氧化應(yīng)激（oxidativestress, OS）狀態(tài)。OS與很多疾病包括腎臟疾病的發(fā)生、發(fā)展密不可分。OS狀態(tài)時(shí)，SOD2表達(dá)增加，這可以降低OS對(duì)組織造成的損傷。OS損傷的標(biāo)志物多種多樣，其中8-羥基脫氧鳥(niǎo)苷（8-hydroxy-2'-deoxyguanosine,8-OHdG）是DNA損害的敏感標(biāo)志物。在疾病或某些外源性物質(zhì)刺激下活性氧類(lèi)(Reactive Oxygen Species, ROS)快速釋放并在體內(nèi)過(guò)度蓄積，致OS超出機(jī)體抗氧化能力而造成DNA的氧化損傷。另有研究發(fā)現(xiàn)，IMN患者腎組織中的SOD2可能作為足細(xì)胞的特異性抗原，參與IMN的發(fā)病過(guò)程，促進(jìn)IMN的進(jìn)展。因此研究SOD2在IMN患者腎組織中表達(dá)是很有必要的。本課題旨在研究SOD2在IMN患者腎組織內(nèi)表達(dá)及意義，及其與IgG4表達(dá)部位的聯(lián)系，并檢測(cè)患者血、尿標(biāo)本中8-OHdG的表達(dá)水平，探討OS在IMN發(fā)病中的作用，，進(jìn)一步揭示IMN的發(fā)病機(jī)制，為指導(dǎo)臨床治療和觀察預(yù)后提供依據(jù)。 方法：病例來(lái)源于2013年6月至2013年12月河北醫(yī)科大學(xué)第三醫(yī)院腎內(nèi)科病房診治的41例IMN住院患者，所有患者均為首次經(jīng)腎穿刺活檢病理檢查確診者。收集首次經(jīng)腎穿刺活檢病理檢查確診的繼發(fā)性膜性腎�。⊿econdary Membranous Nephropathy, SMN）住院患者13例和微小病變性腎病(minimal change disease, MCD)住院患者6例為對(duì)照組。應(yīng)用免疫組織化學(xué)方法檢測(cè)IMN組、SMN組和MCD組患者腎組織中SOD2及IgG4的表達(dá)部位，結(jié)果通過(guò)圖像分析系統(tǒng)（Image-ProPlus, IPP）進(jìn)行半定量分析。同時(shí)收集IMN組、SMN組和MCD組患者晨起的血液及尿液標(biāo)本，應(yīng)用ELISA定量方法檢測(cè)血液及尿液標(biāo)本中8-OHdG的表達(dá)水平，并探討SOD2與8-OHdG表達(dá)的相關(guān)性。應(yīng)用SPSS17.0統(tǒng)計(jì)學(xué)軟件對(duì)實(shí)驗(yàn)數(shù)據(jù)進(jìn)行統(tǒng)計(jì)學(xué)處理， P＜0.05時(shí)差異有統(tǒng)計(jì)學(xué)意義，計(jì)量資料用均數(shù)±標(biāo)準(zhǔn)差(x±s)表示，計(jì)數(shù)資料采用率或構(gòu)成比表示。正態(tài)分布資料多組間均數(shù)比較采用方差分析，多重比較采用SNK-q檢驗(yàn)。相關(guān)性檢驗(yàn)采用直線相關(guān)分析。 結(jié)果：SOD2在IMN組、SMN組和MCD組患者腎組織腎小管上皮細(xì)胞均有表達(dá)，表達(dá)無(wú)明顯差異；SOD2在SMN組、MCD組患者腎組織腎小球中未見(jiàn)表達(dá)；SOD2在IMN組患者腎組織腎小球基底膜、足細(xì)胞和上皮下均有一定表達(dá)。IMN組患者腎組織腎小球內(nèi)SOD2的表達(dá)較SMN組、MCD組均顯著增強(qiáng)（P0.01）。IgG4在SMN組、MCD組患者腎組織中未見(jiàn)表達(dá)；IgG4在大部分IMN組患者腎組織腎小球基底膜及上皮下有表達(dá)。IMN組與SMN組、MCD組比較，腎小球內(nèi)IgG4表達(dá)明顯增強(qiáng)（P0.01）。IMN患者腎小球內(nèi)SOD2的表達(dá)與24小時(shí)尿蛋白定量呈負(fù)相關(guān)（r=-0.354，P=0.023，P0.05）；IgG4的表達(dá)與24小時(shí)尿蛋白定量呈正相關(guān)（r=0.361，P=0.021，P0.05）。IMN組、SMN組患者血、尿標(biāo)本中8-OHdG表達(dá)水平較MCD組升高（P0.05）；IMN組與SMN組相比差異無(wú)統(tǒng)計(jì)學(xué)意義（P0.05）。 結(jié)論：①8-OHdG在IMN患者血液及尿液標(biāo)本中表達(dá)水平升高，證實(shí)IMN發(fā)病過(guò)程中存在DNA的氧化損傷，提示OS參與了IMN的發(fā)生和發(fā)展。②SOD2在IMN腎組織中表達(dá)增高，且與24小時(shí)尿蛋白定量呈負(fù)相關(guān)，提示SOD2作為抗氧化金屬酶，在腎臟OS時(shí)對(duì)機(jī)體起保護(hù)作用，降低尿蛋白的產(chǎn)生。但SOD2與IgG4均在IMN腎小球上皮下沉積，推測(cè)SOD2可能作為足細(xì)胞致病抗原參與IMN的發(fā)病過(guò)程。③SOD2在IMN和SMN中表達(dá)不同，提示IMN與SMN的發(fā)病機(jī)制不同。
[Abstract]:Objective: membranous nephropathy (MN) is one of the most common pathological types of adult nephrotic syndrome (nephrotic syndrome (NS)). According to statistics, about 75% of adult cases are mainly idiopathic membranous nephropathy (idiopathic membranous nephropathy, IMN), and 25% of the cases are secondary to a variety of causes, including tumors. .1/4-1/3IMN patients with infection, autoimmune diseases, metabolic diseases, drugs and poison damage can be completely or partially relieved. The spontaneous remission rate of patients with large albuminuria is about 20%, and the rest of the patients will slow to end-stage renal disease or die from complications and other diseases after 5-16 years. In recent years, the incidence of IMN It is increasing year by year, but the research on its specific pathogenesis is still not very thorough. It is generally believed that the body is pathogenic to the specific IgG4 antibody of the renal podocytes and forms the upper subcutaneous immune complex. Therefore, it is of great significance to clarify the pathogenesis of IMN, and will provide new help for the diagnosis and treatment of the disease.
Manganese superoxide dismutase (manganese superoxide dismutase, SOD2) is an important component of a wide range of antioxidant cell protection systems. It is an antioxidant enzyme, which can convert toxic superoxide anion into hydrogen peroxide and diatomic oxygen. It plays a vital role in the oxidation and antioxidant balance of the body. When a variety of harmful stimuli are subjected, the high active molecules in the body produce too much, the oxidation system and the antioxidant system are unbalanced, making the body in the state of oxidative stress (oxidativestress, OS).OS and the occurrence of many diseases including kidney disease. When the development of the inseparable.OS state, the SOD2 table increases, which can reduce the OS damage to the tissue caused by.OS damage. 8- hydroxyl deoxy guanosine (8-hydroxy-2'-deoxyguanosine, 8-OHdG) is a sensitive marker of DNA damage. The reactive oxygen species (Reactive Oxygen Species, ROS) is released rapidly and overaccumulated in the body under the condition of disease or some exogenous substances, causing OS beyond the body's antioxidant capacity to cause oxidative damage to DNA. Other studies have found that SOD2 in the renal tissue of IMN patients may be a specific antigen of the podocyte, participate in the pathogenesis of IMN and promote the progress of IMN. Therefore, it is necessary to study the expression of SOD2 in the renal tissue of the patients with IMN. The purpose of this study is to study the significance of SOD2 in the renal tissue of IMN patients and the relationship with the IgG4 expression site. To detect the expression level of 8-OHdG in the blood and urine samples of patients, to explore the role of OS in the pathogenesis of IMN, to further reveal the pathogenesis of IMN, and to provide the basis for guiding clinical treatment and observing the prognosis.
Methods: the cases were derived from 41 IMN hospitalized patients in the nephrology ward of the Third Hospital of Hebei Medical University from June 2013 to December 2013. All patients were confirmed by the first biopsy of the renal biopsy. The first secondary membranous nephropathy (Secondary Membranous Nephropathy, SMN) was collected for the first time by biopsy of the renal biopsy (SMN). 13 hospitalized patients and 6 patients with minimal change disease (MCD) were in the control group. The immunohistochemical method was used to detect the expression of SOD2 and IgG4 in group IMN, SMN and MCD groups, and the results were semi quantitative analyzed by the image analysis system (Image-ProPlus, IPP). Meanwhile, the IMN group was collected. The blood and urine samples from group MCD and group MCD were measured by ELISA quantitative method, and the correlation between the expression of SOD2 and 8-OHdG was investigated. The data of the experimental data were statistically processed with SPSS17.0 statistics software. The difference was statistically significant when P < 0.05, and the mean number of measurement data was standardized. The difference (x + s) was expressed as a representation of the ratio or composition of the count data. The average number of normal distribution data was compared with the analysis of variance, and the multiple comparison used the SNK-q test. The correlation test was based on the linear correlation analysis.
Results: SOD2 was expressed in renal tubular epithelial cells in group IMN, SMN and MCD, and there was no obvious difference in the expression of renal tubular epithelial cells. In group SMN, there was no expression of renal glomerulus in group MCD; SOD2 in the renal tissue of group IMN, renal glomerular basement membrane, podocyte and epithelia, there was certain expression of renal glomerular SOD2 in the patients with group.IMN. The expression of MCD in group SMN was significantly enhanced (P0.01).IgG4 in group SMN, group MCD was not expressed in renal tissue, IgG4 was expressed in renal glomerular basement membrane and subcutaneous tissue in most of IMN patients, and.IMN group and SMN group were expressed in the renal glomerular basement membrane and MCD group. The expression of protein was negatively correlated (r=-0.354, P=0.023, P0.05), and the expression of IgG4 was positively correlated with the 24 hour urinary protein (r=0.361, P=0.021, P0.05).IMN group. The expression level of 8-OHdG in the SMN group was higher than that in the MCD group (P0.05).
Conclusion: (1) the expression level of 8-OHdG in the blood and urine specimens of patients with IMN is elevated, which confirms the oxidative damage of DNA during the pathogenesis of IMN, suggesting that OS participates in the occurrence and development of IMN. (2) the expression of SOD2 in the renal tissue of IMN is higher and is negatively related to the quantitative 24 hour urine protein, suggesting that SOD2 is used as an antioxidant enzyme and in the kidney OS of the body. It plays a protective role to reduce the production of urine protein. But both SOD2 and IgG4 are deposited subcutaneously on IMN glomeruli. It is suggested that SOD2 may participate in the pathogenesis of IMN as a pathogenetic antigen of podoni. (3) the expression of SOD2 in IMN and SMN is different, suggesting that the pathogenesis of IMN and SMN is different.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R692

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