本文選題：自發(fā)性高血壓　切入點(diǎn)：纈沙坦　出處：《遵義醫(yī)學(xué)院》2017年碩士論文

【摘要】：目的:觀察纈沙坦對(duì)自發(fā)性高血壓大鼠(SHR)血壓的影響,并檢測(cè)大鼠腎臟水通道蛋白-1、2、5(AQP1、AQP2、AQP5)m RNA和蛋白的表達(dá)變化,為纈沙坦治療高血壓的藥效學(xué)機(jī)制提供新的理論依據(jù),并為抗高血壓藥的研發(fā)提供可能的作用靶點(diǎn)。方法:自發(fā)性高血壓大鼠(SHR)和Wistar Kyoto(WKY)大鼠分別12只,隨機(jī)分為纈沙坦灌胃組(SHR-V組、WKY-V組)和生理鹽水灌胃組(SHR-N組、WKY-N組),每組各6只。灌胃劑量:纈沙坦為每天10mg/kg體重,生理鹽水為換算出的不含纈沙坦的相應(yīng)體積。每周稱量大鼠體重并以此調(diào)整一次藥物劑量,用無(wú)創(chuàng)血壓儀測(cè)量尾動(dòng)脈收縮壓一次,持續(xù)至第40周時(shí)腹主動(dòng)脈采血并收集腎臟,用ELISA和化學(xué)發(fā)光法分別測(cè)定血漿精氨酸加壓素(AVP)和血管緊張素Ⅱ(AngⅡ)濃度,用蘇木素-伊紅(HE)染色,觀察各組大鼠腎臟形態(tài)學(xué)變化,用實(shí)時(shí)熒光定量PCR和Western blot分別檢測(cè)腎臟AQP1,2,5 m RNA和蛋白的表達(dá)變化,用免疫組織化學(xué)(IHC)法觀測(cè)腎臟AQP1,2,5蛋白的定位和表達(dá)。結(jié)果:1.SHR血壓值在第12周開始灌胃時(shí)明顯高于WKY大鼠;在第16周時(shí)SHR-V組血壓值比SHR-N組已有明顯降低(P0.05);第40周時(shí),血壓進(jìn)一步降低,但仍明顯高于WKY-N組和WKY-V組,而WKY-N組與WKY-V組之間無(wú)明顯差異(P0.05)。2.第40周血漿AngⅡ濃度:SHR-V組比SHR-N組、WKY-V比WKY-N組均明顯升高(P0.05);SHR-N組比WKY-N組、SHR-V組比WKY-V組均略有升高,但無(wú)統(tǒng)計(jì)學(xué)意義。血漿AVP濃度:SHR-V組比SHR-N組明顯降低(P0.05);WKY-V組比WKY-N組明顯升高(P0.05);而SHR-N組比WKY-N組、SHR-V組比WKY-V組均明顯降低(P0.05)。3.第40周腎臟HE染色顯示,WKY-N組與WHY-V組腎小球毛細(xì)血管壁薄,基底膜未見明顯增厚,腎小管腔刷狀緣及腎小囊腔清晰可見。SHR-N組可見部分腎小球增大,腎小管管腔及毛細(xì)血管擴(kuò)張,部分腎小球萎縮,囊腔內(nèi)分葉狀增多,毛細(xì)血管結(jié)構(gòu)不清,系膜細(xì)胞及基質(zhì)增生,腎小管間質(zhì)增多,管腔變窄,SHR-V組中上述病變明顯減輕。4.第40周腎臟RT-PCR結(jié)果顯示,SHR-V組比SHR-N組AQP1,2,5 m RNA相對(duì)表達(dá)量均明顯升高(P0.05);WKY-V組比WKY-N組均無(wú)明顯改變(P0.05);SHR-N組比WKY-N組AQP1,5明顯降低(P0.05),而AQP2則明顯升高(P0.05);SHR-V組比WKY-V組AQP1,5無(wú)明顯變化(P0.05),而AQP2則明顯升高(P0.05)。5.第40周腎臟Western blot結(jié)果顯示,SHR-V組比SHR-N組AQP1,2,5相對(duì)灰度值均明顯升高(P0.05);WKY-V組比WKY-N組AQP1,2,5均無(wú)明顯改變(P0.05);SHR-N組比WKY-N組AQP1,5明顯降低(P0.05),而AQP2則無(wú)明顯改變(P0.05);SHR-V組比WKY-V組AQP1,2,5均無(wú)明顯改變(P0.05)。6.第40周腎臟IHC結(jié)果顯示,AQP1在皮質(zhì)主要表達(dá)于近端小管,在髓質(zhì)主要表達(dá)于髓袢降支細(xì)段,WKY-N組平均光密度值皮質(zhì)明顯高于髓質(zhì)(P0.05),WKY-V組以及SHR-V組皮質(zhì)均明顯低于髓質(zhì)(P0.05),SHR-N組則無(wú)明顯差異(P0.05);AQP2在皮質(zhì)主要表達(dá)于連接小管和皮質(zhì)集合管,在髓質(zhì)主要表達(dá)于髓質(zhì)集合管,WKY-N組、WKY-V組、SHR-N組以及SHR-V組皮質(zhì)平均光密度值均明顯低于髓質(zhì)(P0.05);AQP5在皮質(zhì)主要表達(dá)于連接小管和皮質(zhì)集合管,在髓質(zhì)主要表達(dá)于髓質(zhì)集合管,WKY-N組、WKY-V組、SHR-N組以及SHR-V組皮質(zhì)平均光密度值均明顯低于髓質(zhì)(P0.05)。結(jié)論:1.在自發(fā)性高血壓后期,SHR腎臟內(nèi)局部RAS更加活躍,AVP的體液調(diào)節(jié)作用相對(duì)增強(qiáng),纈沙坦可以使SHR的體液調(diào)節(jié)效應(yīng)進(jìn)一步加強(qiáng)。2.血壓的長(zhǎng)期變化過程會(huì)引起大鼠腎臟AQP1在皮質(zhì)與髓質(zhì)間的重新分布,纈沙坦可以改變SHR AQP1皮質(zhì)與髓質(zhì)間的平均分布狀態(tài),使髓質(zhì)表達(dá)增多。3.AQP2在大鼠腎臟的分布皮質(zhì)低于髓質(zhì),纈沙坦能夠顯著提高SHR腎臟內(nèi)AQP2 m RNA的表達(dá),而蛋白表達(dá)升高相對(duì)緩慢。4.AQP5在大鼠腎內(nèi)的分布皮質(zhì)低于髓質(zhì),纈沙坦能顯著提高SHR腎臟AQP5m RNA和蛋白的表達(dá)量。
[Abstract]:Objective: To observe the effect of valsartan on spontaneously hypertensive rats (SHR) the influence of blood pressure, and the detection of renal aquaporins in rats with -1,2,5 (AQP1, AQP2, AQP5) expression of M protein and RNA, provide a new theoretical basis for the efficacy of valsartan in the treatment of hypertension mechanism and provide potential targets for the development of resistance the treatment of hypertension. Methods: spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were 12 rats were randomly divided into valsartan gavage group (SHR-V group, WKY-V group) and saline group (SHR-N group, WKY-N group), 6 rats in each group. Intragastric dose of valsartan for: every 10mg/kg weight, normal saline was calculated without the corresponding volume weight per week. Valsartan weighed rats and to adjust doses, with non-invasive blood pressure measurement of systolic blood pressure once, continued to fortieth weeks of abdominal aorta and kidney were collected by ELISA and chemical. Measured plasma arginine vasopressin chemiluminescence (AVP) and angiotensin II (Ang II) concentration, with hematoxylin eosin (HE) staining, observe the morphological changes of kidney of rats were detected the expression change of M renal AQP1,2,5 RNA and protein by real-time quantitative PCR and Western blot, with immunohistochemical (IHC) localization and expression of AQP1,2,5 protein in kidney was observed. Results: 1.SHR blood pressure values in twelfth week mice was significantly higher than that of WKY rats; at sixteenth weeks, the blood pressure in the SHR-V group was significantly lower than SHR-N group (P0.05); for fortieth weeks, the blood pressure decreased further, but still significantly higher than WKY-N group and WKY-V group, but no significant difference between group WKY-N and group WKY-V (P0.05).2. fortieth week plasma Ang II: SHR-V group than in the SHR-N group, the WKY-V ratio was significantly increased in the WKY-N group (P0.05); SHR-N group than in the WKY-N group, SHR-V group than in the WKY-V group were slightly increased, but no statistical significance Yi. The concentration of plasma AVP in SHR-V group was significantly lower than that of group SHR-N (P0.05); WKY-V group was significantly higher than that in WKY-N group (P0.05); and SHR-N group than in the WKY-N group, SHR-V group than in WKY-V group was significantly lower (P0.05).3. fortieth weeks of renal HE staining showed that WKY-N group and WHY-V group glomerular capillary wall thin basement membrane was thicker, tubular brush border and renal cysts visible.SHR-N group showed partial glomerular enlargement, renal tubular lumen and telangiectasia, partial glomerular atrophy, lobulated cystic cavity increased, capillary structure is not clear, mesangial cells and matrix hyperplasia, tubulointerstitial increased lumen narrowing in the SHR-V group, the lesion was reduced fortieth weeks of.4. kidney RT-PCR results showed that the SHR-V AQP1,2,5 M group than in the SHR-N group the relative expression of RNA were significantly increased (P0.05); WKY-V group than in the WKY-N group showed no significant change (P0.05); SHR-N group was significantly reduced than the WKY-N group AQP1,5 Low (P0.05), while AQP2 increased significantly (P0.05); SHR-V group than in the WKY-V group there was no significant change in AQP1,5 (P0.05), and AQP2 (P0.05).5. significantly increased fortieth weeks of renal Western blot results showed that the SHR-V group than in the SHR-N group relative gray scale values of AQP1,2,5 were significantly increased (P0.05); group WKY-V than WKY-N group AQP1,2,5 showed no significant change (P0.05); SHR-N group was significantly lower than in group WKY-N (P0.05), AQP1,5 and AQP2 were not significantly changed (P0.05); SHR-V group than in WKY-V group AQP1,2,5 showed no significant change (P0.05.6.) fortieth weeks of renal IHC showed that AQP1 was mainly expressed in the cortex in the proximal tubule, in the medulla is mainly expressed in the thin descending limb of Henle, WKY-N group was significantly higher than that of the average optical density of cortical medulla (P0.05), WKY-V group and SHR-V group were significantly lower than that of the medulla cortex (P0.05), there was no obvious difference between the SHR-N group (P0.05); AQP2 was mainly expressed in the cortex in the connecting tubule and cortical collecting duct in the medulla the main The expression in the medullary collecting duct, WKY-N group, WKY-V group, SHR-N group and SHR-V group, the average optical density value of cortex was significantly lower than that of the medulla (P0.05); AQP5 was mainly expressed in the cortex in the connecting tubule and cortical collecting duct in the medulla is mainly expressed in the medullary collecting duct, WKY-N group, WKY-V group, SHR-N group and SHR-V group of cortex the average optical density values were significantly lower than that of the medulla (P0.05). Conclusion: 1. in the late SHR in the kidney of spontaneously hypertensive, local RAS was more active, relatively enhanced AVP humoral regulation effect of valsartan can make SHR humoral regulation effect to further strengthen the long-term changes of blood pressure of.2. process will cause redistribution in AQP1 rat kidney cortex and medulla the average distribution of valsartan can change the SHR AQP1 between the cortex and medulla, the increased expression of.3.AQP2 in cortex medulla distribution of rat kidney medulla below, valsartan can significantly improve SHR in the kidney of AQP 2, the expression of M RNA was increased, while protein expression increased slowly. The distribution of.4.AQP5 in rat kidneys was lower than that in medulla. Valsartan significantly increased the expression of AQP5m RNA and protein in SHR kidney.

【學(xué)位授予單位】：遵義醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R544.1

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