【摘要】：背景近年來(lái),隨著高血壓的發(fā)病率逐年上升,高血壓靶器官損害越來(lái)越受到人們的關(guān)注,高血壓腎臟損害是高血壓常見(jiàn)的靶器官損害之一,其機(jī)制不明確。睪酮是機(jī)體內(nèi)重要的雄性激素之一,國(guó)內(nèi)外多項(xiàng)研究已證實(shí)其與心血管疾病密切相關(guān)。睪酮的生物學(xué)活性是通過(guò)睪酮受體實(shí)現(xiàn)的,睪酮受體(androgen receprtor,AR)表達(dá)水平的變化與多種疾病的發(fā)生發(fā)展相關(guān)。但關(guān)于其在高血壓腎損害中的地位作用及其信號(hào)轉(zhuǎn)導(dǎo)機(jī)制不清。已知,絲裂素活化蛋白激酶(mitogen-activated protein kinases,MAPKs)是絲/蘇氨酸蛋白激酶中的一種,MAPKs的過(guò)度激活在高血壓腎損害的發(fā)生、發(fā)展中發(fā)揮重要作用。絲裂素活化蛋白酶磷酸酶1(mitogen-activated protein kinase phosphatase-1,MKP-1)是MAPK的特異性調(diào)節(jié)磷酸酶,可使磷酸化的MAPK失活。國(guó)內(nèi)外多個(gè)研究小組發(fā)現(xiàn),AR與MAPKs偶聯(lián)多種疾病的發(fā)生發(fā)展。我課題組以往的研究證實(shí),AR可能與MAPKs相偶聯(lián)共同參與高血壓心肌重構(gòu)的過(guò)程。在高血壓腎臟損害中,是否也存在有AR的參與?其是否與MAPKs信號(hào)轉(zhuǎn)導(dǎo)通路有關(guān),未見(jiàn)相關(guān)報(bào)道。目的探討AR在高血壓腎臟損害中的作用并初步探討其作用機(jī)制。方法按照隨機(jī)對(duì)照原則將30只28日齡雄性Wistar大鼠分為正常對(duì)照組、假手術(shù)對(duì)照組和高血壓組,每組10只�！皟赡I一夾法”建立左腎動(dòng)脈狹窄的腎血管性高血壓大鼠模型;假手術(shù)組僅打開(kāi)腹腔不做結(jié)扎處理;正常對(duì)照組無(wú)處理。采用Tail-Cuff法測(cè)量各組大鼠不同時(shí)期尾鼠尾動(dòng)脈收縮壓(systolic blood pressure,SBP);采用蘇木精伊紅(hematoxylin eosin stain,HE)染色法觀察各組大鼠左右腎臟的組織形態(tài)結(jié)構(gòu)變化;采用免疫組化法檢測(cè)三組大鼠右腎組織中AR蛋白及MKP-1蛋白的表達(dá)水平。結(jié)果1.正常對(duì)照組大鼠SBP無(wú)明顯變化(P0.05),左右腎臟組織形態(tài)大致正常;2.假手術(shù)對(duì)照組大鼠SBP無(wú)明顯變化(P0.05),左右腎臟形態(tài)學(xué)觀察無(wú)明顯改變;與正常對(duì)照組相比,假手術(shù)對(duì)照組右腎組織中AR及MKP-1蛋白表達(dá)水平無(wú)明顯變化(P0.05);3.高血壓組大鼠造模后SBP明顯增高(F組間=1211.779,F時(shí)間=1613.225,F交互=1537.050,P0.001);與正常對(duì)照組相比,高血壓組大鼠右腎重構(gòu);與正常對(duì)照組相比,高血壓組大鼠右腎組織中AR和MKP-1蛋白表達(dá)水平明顯下降(P0.001);4.在高血壓組大鼠右腎組織中AR與MKP-1蛋白表達(dá)水平的呈線性正相關(guān)(r=0.744,P=0.014),在正常對(duì)照組和假手術(shù)對(duì)照組無(wú)明顯相關(guān)(r=0.457和0.436,P0.05)結(jié)論1.高血壓腎臟損害過(guò)程中存在AR蛋白表達(dá)水平的改變。2.AR蛋白可能與MAKPs信號(hào)轉(zhuǎn)導(dǎo)通路相偶聯(lián)共同參與高血壓腎臟損害的過(guò)程。
[Abstract]:Background in recent years, with the incidence of hypertension rising year by year, hypertension target organ damage has attracted more and more attention. Hypertensive kidney damage is one of the common target organ damage in hypertension, and its mechanism is unclear. Testosterone is one of the most important androgens in the body. Many studies at home and abroad have proved that testosterone is closely related to cardiovascular disease. The biological activity of testosterone is realized by testosterone receptor. The change of testosterone receptor (androgen receprtor,AR) expression level is related to the occurrence and development of many diseases. However, its role in hypertensive renal damage and its signal transduction mechanism are unclear. It is known that mitogen-activated protein kinase (mitogen-activated protein kinases,MAPKs) is one of the mitogen / threonine protein kinases. Excessive activation of MAPKs plays an important role in the pathogenesis and development of hypertensive renal damage. Mitogen-activated protease 1 (mitogen-activated protein kinase phosphatase-1,MKP-1) is a phosphatase specifically regulated by MAPK, which inactivates phosphorylated MAPK. Many research groups at home and abroad have found that AR is coupled with MAPKs in the occurrence and development of many diseases. Our previous studies have confirmed that AR may be coupled with MAPKs in the process of hypertensive myocardial remodeling. Is there any involvement of AR in hypertensive kidney damage? Whether it is related to MAPKs signal transduction pathway has not been reported. Objective to investigate the role of AR in hypertensive renal damage and its mechanism. Methods Thirty 28 day old male Wistar rats were randomly divided into normal control group, sham operation control group and hypertension group with 10 rats in each group. The rat model of renal vascular hypertension with left renal artery stenosis was established by "two kidneys and one clip method", the sham operation group only opened the abdominal cavity without ligation, and the normal control group did not. The systolic blood pressure (systolic blood pressure,SBP) of caudal artery was measured by Tail-Cuff method and the changes of left and right kidneys were observed by hematoxylin eosin (hematoxylin eosin stain,HE) staining. The expression of AR protein and MKP-1 protein in the right kidney of the three groups were detected by immunohistochemical method. Result 1. There was no significant change in SBP in normal control group (P0.05), and left and right renal tissue morphology was approximately normal; 2. There were no significant changes in SBP and left and right kidney morphology in sham-operated control group (P0.05). Compared with normal control group, the expression of AR and MKP-1 protein in right kidney of sham-operated control group had no significant change (P0.05). 3. The SBP of the hypertensive group was significantly higher than that of the normal control group (F = 1211.779F = 1613.225F interaction = 1537.050p 0.001), and the right renal remodeling in the hypertensive group was significantly higher than that in the normal control group. Compared with the normal control group, the expression of AR and MKP-1 protein in the right kidney of hypertensive rats decreased significantly (P0. 001); 4. There was a linear positive correlation between the expression of AR and MKP-1 protein in the right kidney tissue of hypertensive rats (r = 0.744), but there was no significant correlation between normal control group and sham operation control group (r = 0.457 and 0.436P 0.05). Conclusion 1. There is a change in the expression of AR protein during renal injury in hypertension. 2.AR protein may be coupled with MAKPs signal transduction pathway to participate in the process of hypertensive renal damage.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R692;R544.1

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