本文選題：腎間質(zhì)纖維化 + 單側(cè)輸尿管梗阻（unilateral��； 參考：《河北醫(yī)科大學(xué)》2014年碩士論文

【摘要】：目的：腎小管間質(zhì)纖維化是由各種慢性進(jìn)展性腎臟疾病不可避免的最終結(jié)局。腎間質(zhì)纖維化的發(fā)生發(fā)展過程復(fù)雜，此過程涉及腎小管間質(zhì)的損傷，炎性細(xì)胞的浸潤，多種炎癥介質(zhì)的產(chǎn)生，纖維母細(xì)胞的增殖，細(xì)胞外基質(zhì)積聚等過程，多種細(xì)胞因子參與其中。 最近幾年里，自噬在腎臟中的作用逐漸為人們所關(guān)注，一系列研究表明，自噬與多種腎臟疾病相關(guān)。既往研究顯示，自噬功能增強通常對腎臟功能保護(hù)有益，然而，在某些情形下，過度的自噬可能造成細(xì)胞凋亡或死亡。近年來對腎臟有關(guān)自噬方面的研究多集中腎小球上皮細(xì)胞、腎臟系膜細(xì)胞方面，對于腎小管細(xì)胞的研究多限于缺血-再灌注損傷、藥物性腎損害,而對于梗阻性腎病與自噬的相關(guān)研究較少。 目前普遍認(rèn)為，自噬的誘導(dǎo)由哺乳動物雷帕霉素靶蛋白（mTOR）所調(diào)控，mTOR是一種非典型的絲氨酸激酶，在進(jìn)化上十分保守，廣泛存在于各種哺乳動物中，可調(diào)節(jié)細(xì)胞增殖、生長以及自噬。當(dāng)細(xì)胞處于營養(yǎng)充足或缺少應(yīng)激信號的狀態(tài)時，mTOR激活，自噬受到抑制。然而，一旦處于營養(yǎng)缺乏或者是應(yīng)激狀態(tài)，mTOR活性下降或受到抑制，自噬進(jìn)程啟動。細(xì)胞饑餓時誘導(dǎo)自噬的目的在于降解細(xì)胞內(nèi)蛋白質(zhì)，最終獲得氨基酸再度為細(xì)胞供應(yīng)新的能量來源。 當(dāng)mTOR活性下降時，自噬相關(guān)蛋白（Atg）13去磷酸化，允許其與另一個Atg形成活化聚合物Atg1。該聚合物啟動了自噬體膜的形成，然后自噬體膜延伸包裹待降解的內(nèi)容物。該膜的延展包括了多種Atg蛋白，其中最重要的是蛋白輕鏈（LC）3，LC3表達(dá)水平被普遍地用作自噬標(biāo)記物，廣泛地應(yīng)用于免疫組化等實驗方法中。 轉(zhuǎn)化生長因子β1(Transforming growth factor, TGF-β1)被認(rèn)為是腎小管間質(zhì)纖維化病理進(jìn)程中的一個中心媒介。它可以促進(jìn)細(xì)胞外基質(zhì)成份大量生成，促進(jìn)炎癥細(xì)胞的活化和趨化活動，介導(dǎo)腎小管上皮細(xì)胞向間充質(zhì)細(xì)胞轉(zhuǎn)化，以及導(dǎo)致腎小球硬化及小管間質(zhì)纖維化，最終發(fā)展至終末期腎衰竭。 雷帕霉素，哺乳動物雷帕霉素靶蛋白（mammalian target of rapamycin,mTOR）信號轉(zhuǎn)導(dǎo)通路抑制劑，是一種由鏈球菌屬產(chǎn)生的大環(huán)內(nèi)酯類抗免疫抗生素，目前主要應(yīng)用于移植后抗排異反應(yīng)。近年來研究發(fā)現(xiàn)，該物質(zhì)在抑制腎間質(zhì)纖維化方面有所成效，這可能與自噬有關(guān)。但目前尚未有研究證明雷帕霉素對梗阻性腎損傷中細(xì)胞自噬有何種程度的影響，梗阻后自噬水平與時間的變化有著何種關(guān)聯(lián)，以及其與腎臟纖維化之間的關(guān)系。因此，本實驗擬通過對SD大鼠建立單側(cè)輸尿管梗阻(unilateral urethralobstruction, UUO)模型，應(yīng)用雷帕霉素進(jìn)行干預(yù)，結(jié)合免疫組織化學(xué)等手段，觀察不同實驗組中，TGF-β1、LC3、mTOR表達(dá)隨時間所發(fā)生的變化，探討雷帕霉素對腎間質(zhì)纖維化的潛在保護(hù)作用，探索腎間質(zhì)纖維化治療的新靶點，為腎間質(zhì)纖維化的臨床防治探索新的可能方向。 方法：健康雄性SD大鼠，，SPF級，體重（180±20）克，54只，經(jīng)過1周適應(yīng)性喂養(yǎng)后，進(jìn)行隨機分組如下：1、對照組(A組)；2、UUO模型組(B組)；3、雷帕霉素治療組(C組)；每組各18只。分別于術(shù)后第3、7、14天隨機選取6只大鼠取出其梗阻側(cè)腎臟組織，分別為D3、D7、D14組，每組各6只。手術(shù)過程：B、C組大鼠給予10%水合氯醛（0.1ml/kg）腹腔注射+2%鹽酸利多卡因皮下麻醉。備皮消毒鋪單后，給予左側(cè)腹部縱形切口，暴露左腎下極后，沿之尋找左側(cè)輸尿管，在左側(cè)輸尿管中上1/3交界處的上下2處分別用絲線結(jié)扎，并從中上1/3交界處剪斷，以避免逆行感染；而A組除了不結(jié)扎、剪斷輸尿管外，其余過程與B、C二組相同。給藥：從手術(shù)前1天開始，給予各組大鼠每天灌胃1次，每周復(fù)查體重，根據(jù)體重變化調(diào)整給藥量；治療組以雷帕霉素2mg/kg/d劑量灌胃；A組及B組以等容的0.9%NaCl溶液替代雷帕霉素溶液灌胃。實驗期間不限制食水。術(shù)后第3天、7天、14天，分別從A、B、C組中隨機選取6只大鼠取出梗阻腎，4%多聚甲醛固定，石蠟包埋。之后HE染色、Masson染色，以觀察各組大鼠梗阻腎組織病理變化，并采用免疫組織化學(xué)方法測定TGF-β1、mTOR及LC3表達(dá)水平，應(yīng)用圖像分析系統(tǒng)進(jìn)行半定量分析。所有實驗數(shù)據(jù)用SPSS20.0統(tǒng)計分析軟件進(jìn)行統(tǒng)計學(xué)處理，以均數(shù)±標(biāo)準(zhǔn)差(x±ｓ)表示統(tǒng)計結(jié)果，應(yīng)用單因素方差分析對數(shù)據(jù)進(jìn)行分析， P0.05表示結(jié)果有統(tǒng)計學(xué)意義。 結(jié)果：光鏡下HE染色：A組，未見明顯異常；B組，在術(shù)后第3天，可見少量炎癥細(xì)胞在腎間質(zhì)局部浸潤，腎小管有輕度擴張；第7天，可見腎間質(zhì)大量炎癥細(xì)胞浸潤，腎間質(zhì)寬度明顯增加，腎小管明顯擴張，腎小管上皮細(xì)胞變性、壞死；第14天，可見較多腎小管萎縮，腎小管基底膜有彌漫性增厚、皺縮；C組，術(shù)后腎小管間質(zhì)病變隨梗阻時間延長進(jìn)行性加重，其程度較同時相B組的病變程度輕，但仍明顯重于A組。Masson染色：A組，未見明顯異常；B組，在術(shù)后第3天可見腎小管有輕度擴張，膠原纖維較A組有所增加；術(shù)后第7天及第14天，腎小管擴張程度進(jìn)行性加重，膠原纖維顯著增多，間質(zhì)纖維化現(xiàn)象明顯；C組，術(shù)后腎小管擴張程度、膠原纖維表達(dá)水平隨梗阻時間延長進(jìn)行性加重、增多，其較同時相B組的病變程度稍輕，但仍明顯終于A組。免疫組織化學(xué)結(jié)果：(1)TGF-β1： A組，腎小管上皮細(xì)胞中可見少量表達(dá)； B組，腎小管上皮細(xì)胞中可見表達(dá)，隨著梗阻時間的延長，其表達(dá)水平呈進(jìn)行性升高，且與A組同時相相比較均有統(tǒng)計學(xué)差異(P0.05)； C組，TGF-β1的表達(dá)水平與同期B組表達(dá)水平相比較均有顯著下降(P0.05)，但仍高于同期A組中(P0.05)的表達(dá)水平。⑵LC3:A組，存在基礎(chǔ)水平表達(dá)； B組，第3天時腎小管上皮細(xì)胞中出現(xiàn)廣泛水平的表達(dá)，較A組顯著增加(P0.05)，第7天時，其表達(dá)水平較第3天有所下降(P0.05)，第14天，其表達(dá)水平下降接近至基礎(chǔ)水平；C組，第3天時腎小管上皮細(xì)胞中出現(xiàn)廣泛水平的表達(dá)，且較同時期B組表達(dá)水平增高(P0.05)，第7天時有所下降，但仍高于同時期B組之表達(dá)水平(P0.05)，第14天時進(jìn)一步下降，表達(dá)水平仍高于同時期B組(P0.05)。⑶mTOR：A組，在腎小管上皮細(xì)胞中有一定水平的表達(dá)；B組，第3天時，表達(dá)水平較A組顯著下降(P0.05)，第7天時表達(dá)水平較第3天升高(P0.05)，第14天時其表達(dá)水平進(jìn)一步升高(P0.05)；C組，第3天時，其表達(dá)水平較A組顯著下降(P0.05)，較B組同期有所下降，第7、14天時表達(dá)水平較第3天時上升(P0.05)，且隨著梗阻時間延長進(jìn)行性增高；同時相表達(dá)水平較B組同期下降。 結(jié)論：（1）梗阻早期腎小管上皮細(xì)胞自噬水平顯著增加，晚期顯著減少，mTOR表達(dá)趨勢與之相反。提示梗阻早期腎小管細(xì)胞受到輕度損傷時，可能通過抑制mTOR，增強了自噬活性對抗因梗阻所致的損傷，從而自我保護(hù)，而梗阻晚期，腎小管細(xì)胞損傷過于嚴(yán)重失代償，mTOR抑制解除，自噬活性減弱，自我保護(hù)作用失能。（2）雷帕霉素干預(yù)后，整體自噬表達(dá)水平升高，mTOR表水平下降，TGF-β1表達(dá)明顯減少，提示雷帕霉素可能通過阻斷mTOR途徑，增強自噬活性，進(jìn)而減輕單側(cè)輸尿管梗阻大鼠腎小管間質(zhì)纖維化的程度。
[Abstract]:Objective: renal tubulointerstitial fibrosis is an inevitable final outcome of various chronic progressive renal diseases. The process of renal interstitial fibrosis is complicated. This process involves renal tubulointerstitial damage, inflammatory cell infiltration, various inflammatory mediators, fibroblast proliferation, extracellular matrix accumulation and so on. Cytokines are involved in it.
In recent years, the role of autophagy in the kidney has gradually been concerned. A series of studies have shown that autophagy is associated with a variety of renal diseases. Previous studies have shown that enhanced autophagy is usually beneficial to renal function protection. However, in some cases, excessive autophagy can cause apoptosis or death. In recent years, the kidney is related to the kidney. Many studies focus on glomerular epithelial cells, and in the mesangial cells of the kidney, the study of renal tubular cells is limited to ischemia reperfusion injury, drug induced renal damage, and less research on obstructive nephropathy and autophagy.
It is widely believed that the induction of autophagy is regulated by the mammalian rapamycin target protein (mTOR). MTOR is an atypical serine kinase, which is very conservative in evolution and widely exists in various mammals. It can regulate cell proliferation, growth and autophagy. When cells are in a state of sufficient nutrition or lack of stress signals, mTOR stimulated. Living, autophagy is inhibited. However, once the nutritional deficiency or stress state is in the state of stress, the activity of mTOR decreases or is inhibited and the autophagy process starts. The purpose of inducing autophagy during the starvation of cells is to degrade the intracellular protein and eventually obtain the amino acid to supply a new source of energy for the cells.
When the mTOR activity drops, the autophagy related protein (Atg) 13 dephosphorylates, allowing it to form an activated polymer with another Atg Atg1. that starts the formation of the autophagic membrane, and then the autophagic membrane extends to the content of the content to be degraded. The extension of the membrane includes a variety of Atg proteins, the most important of which is the protein light chain (LC) 3, and the LC3 expression of water. Ping is widely used as a marker of autophagy, and is widely used in immunohistochemistry and other experimental methods.
Transforming growth factor beta 1 (Transforming growth factor, TGF- beta 1) is considered to be a central medium in the pathological process of renal tubulointerstitial fibrosis. It can promote the production of extracellular matrix components, promote the activation and chemotaxis of inflammatory cells, mediate the transformation of renal tubular epithelial cells into mesenchymal cells, and lead to glomerular hard. Chemotherapy and tubulointerstitial fibrosis eventually develop to end-stage renal failure.
Rapamycin, a mammalian target of rapamycin (mTOR) signal transduction pathway inhibitor, is a macrolide resistant immuno antibiotic produced by the genus Streptococcus, and is currently mainly used for anti rejection after transplantation. In recent years, it has been found to be effective in inhibiting renal interstitial fibrosis. This may be associated with autophagy, but there has been no study on the extent of the effect of rapamycin on autophagy in the obstructive renal injury, what is the association between the level of autophagy after obstruction and the change of time, and the relationship with renal fibrosis. Therefore, this experiment is to establish unilateral ureteral obstruction in SD rats (Unila Teral urethralobstruction, UUO) model, using rapamycin to intervene, combined with immunohistochemistry, to observe the changes in the expression of TGF- beta 1, LC3, mTOR in different experimental groups, explore the potential protection of rapamycin for renal interstitial fibrosis, explore the new target of renal interstitial fibrosis, as the renal interstitial fiber. The clinical prevention and treatment of vitamin D is a new possible direction.
Methods: healthy male SD rats, SPF grade, weight (180 + 20) g, 54 rats, after 1 weeks of adaptive feeding, were randomly divided into groups as follows: 1, control group (group A), 2, UUO model group (B group), 3, rapamycin group (C group), 18 rats in each group. After 3,7,14 day, 6 rats were randomly selected to take out the obstructed renal tissue, D3 respectively. D7, group D14, each group of 6. Operation process: B, group C rats were given 10% chloral chloral (0.1ml/kg) intraperitoneal injection of lidocaine hydrochloride subcutaneous anesthesia. After preparation of skin disinfection sheet, the left abdomen was given a longitudinal incision and left lower left kidney was exposed to the left ureter, and the 2 upper and lower parts of the upper and lower 1/3 junction in the left ureter were made of silk thread, respectively. Ligation and cut off from the middle and upper 1/3 junction to avoid retrograde infection; while group A, in addition to non ligature and cut off the ureter, the rest of the process was the same as that of group B, C two. Administration: from 1 days before the operation, the rats were given 1 times a day, the weight was retuned to the body weight, and the dosage of rapamycin 2mg/kg/d was administered to the treatment group. In group A and group B, the equal volume 0.9%NaCl solution was replaced by rapamycin solution. During the experiment, water was not restricted. Third days, 7 days, 14 days after the operation, 6 rats were randomly selected from the group A, B, and C to take out the obstructed kidneys, 4% polyformaldehyde fixed, and paraffin embedded. Then HE staining, Masson staining, in order to observe the pathological changes of the renal tissue of the rats in each group, and take the observation of the pathological changes of the rats' obstructive kidneys. The expression level of TGF- beta 1, mTOR and LC3 was measured by immunohistochemical method. Semi quantitative analysis was carried out by the image analysis system. All the experimental data were statistically processed with SPSS20.0 statistical analysis software. The statistical results were expressed with the mean number of standard deviation (x + s), and the data were analyzed by single factor square analysis. The P0.05 results showed that the results were unified. The significance of learning.
Results: HE staining under light microscope: no obvious abnormality was found in group A. In group B, a small amount of inflammatory cells were infiltrated in the renal interstitium and slight dilatation of renal tubules on the third day after operation; on the seventh day, a large number of inflammatory cells in the renal interstitium were infiltrated, the width of the renal interstitium was significantly increased, the renal tubules were dilated, the renal tubular epithelial cells denatured and necrotic; fourteenth days, More renal tubules were atrophied and the basement membrane of renal tubule was diffuse thickening and crinkling. In group C, the renal tubulointerstitial lesions were aggravated with the prolongation of the obstruction time. The degree of renal tubulointerstitial lesions was lighter than that of group B, but it was still significantly heavier in group A than in group A. In group A, there was no obvious abnormality; in group B, the renal tubules were slightly enlarged at the third day after operation. After seventh and 14 days after operation, the dilatation degree of renal tubules was aggravated, the collagen fiber increased significantly and the interstitial fibrosis was obvious. In group C, the degree of renal tubule dilation and the expression of collagen fiber increased with the prolongation of the obstruction time, and the degree of pathological changes in group B was slightly lighter than that of group B at the same time. But still obviously finally A group. Immunohistochemical results: (1) TGF- beta 1:A group, renal tubular epithelial cells can be seen a small amount of expression, B group, renal tubular epithelial cells can be seen in the expression, with the prolongation of the obstruction time, the expression level is progressive, and compared with the A group is statistically significant (P0.05); C group, TGF- beta 1 The level of B was significantly lower than that in the same period of the same period (P0.05), but still higher than the expression level of the A group (P0.05) in the same period. (2) LC3:A group, there was a basic level of expression; in group B, there was a wide level expression in the renal tubular epithelial cells at third days, which was significantly increased in the A group (P0.05). At the seventh day, the expression level was lower than that of the third day. (P0.05), on the fourteenth day, the decrease of expression level was close to the base level; in group C, the expression of renal tubular epithelial cells was widely expressed in third days, and the expression level of B group was higher than that of the same period (P0.05), and decreased at seventh days, but it was still higher than that of B group at the same time (P0.05). The expression level was further lower than that in the same period, and the expression level was still higher than that at the same time. In group B (P0.05). (3) mTOR:A, there was a certain level of expression in the renal tubular epithelial cells; in group B, the expression level was significantly lower than that in the A group (P0.05) at third days (P0.05), the expression level was higher than that of the third day (P0.05), and the expression level was further increased at fourteenth days (P0.05), and in the C group, the expression level was significantly lower than that of the A group (P0.05), compared with B in the A group (P0.05), compared with B, and B. At the same time, the expression level of the group decreased at the 7,14 day (P0.05) and increased with the prolongation of the obstruction time, and the expression level of the phase was lower than that of the B group at the same time.
Conclusion: (1) the autophagy level of renal tubular epithelial cells increased significantly in early stage of obstruction, significantly decreased in late stage, and the opposite of mTOR expression. It suggests that the early obstruction of renal tubule cells may enhance the autophagy activity against the obstruction caused by obstruction during the early stage of obstruction of renal tubule, and thus protect the renal tubule cells in the late stage of the obstruction, and the renal tubule cells are late. The damage was too serious, mTOR was relieved, autophagic activity was weakened, and the self protective effect was impaired. (2) after rapamycin, the level of autophagy increased, the level of mTOR decreased, and the expression of TGF- beta 1 decreased significantly. It suggested that rapamycin may enhance autophagic activity by blocking the mTOR pathway, and thus alleviated the kidney of unilateral ureteral obstruction in rats. The degree of tubulointerstitial fibrosis.

【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R693;R692.6

【共引文獻(xiàn)】

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