本文選題：UUO　切入點：腎臟纖維化　出處：《華中科技大學》2016年博士論文

【摘要】：研究背景腎臟纖維化是各種慢性腎臟病終末期共同的病理改變,主要的病理特征是腎小球硬化和腎間質(zhì)纖維化。腎臟纖維化的產(chǎn)生是由于細胞外基質(zhì)過度沉積,超出了腎臟的清除能力,最終造成腎病終末期(ESRD)不可逆的病理改變。目前并沒有針對腎臟纖維化有效的治療方法,ESRD患者只能依靠終身透析和腎臟移植維持生命。有大量充分的證據(jù)表明腎臟系膜細胞和成纖維細胞的活化、腎小管上皮細胞-間充質(zhì)轉(zhuǎn)化(EMT)、炎癥細胞(單核細胞、巨噬細胞和T淋巴細胞)的浸潤以及細胞的凋亡是引起腎臟纖維化重要的細胞機制。TGFβ及下游信號調(diào)節(jié)蛋白Smad的活化很早之前就已經(jīng)被證實是促進腎臟纖維化形成最重要的分子調(diào)節(jié)機制,但是腎臟纖維化形成相關(guān)的細胞活化機制以及TGFβ表達的誘發(fā)因素并沒有完全闡述清楚。內(nèi)質(zhì)網(wǎng)(ER)是細胞內(nèi)參與蛋白質(zhì)合成、轉(zhuǎn)運和修飾,以及脂質(zhì)合成和Ca2+儲存重要的細胞器。當細胞受到諸如氧化應(yīng)激,缺血和缺氧等刺激時,內(nèi)質(zhì)網(wǎng)穩(wěn)態(tài)遭到破壞,影響蛋白質(zhì)的折疊,并最終引起內(nèi)質(zhì)網(wǎng)應(yīng)激(ER stress)的發(fā)生,持續(xù)存在而無法及時得到處理的內(nèi)質(zhì)網(wǎng)應(yīng)激會誘導細胞的程序性死亡,即凋亡。大量文獻證實,內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)的細胞凋亡是機體遭受損傷后器官和組織重構(gòu)的影響因素。例如,在心肌纖維化和肝臟纖維化形成過程中,內(nèi)質(zhì)網(wǎng)應(yīng)激被證實發(fā)揮了關(guān)鍵的調(diào)節(jié)作用。然而,內(nèi)質(zhì)網(wǎng)應(yīng)激在腎臟纖維化病理過程的具體調(diào)節(jié)機制并未有研究進行闡述。目前僅有Chiang等人利用大鼠腎臟纖維化的模型研究證實為內(nèi)質(zhì)網(wǎng)應(yīng)激確實是腎臟纖維化形成的促進因素,并利用內(nèi)質(zhì)網(wǎng)應(yīng)激抑制劑證實腎臟細胞的凋亡程度與腎臟纖維化的程度是成正比的。綜合上述結(jié)論,我們首次在慢性腎臟病患者腎臟纖維化形成過程中進行了內(nèi)質(zhì)網(wǎng)應(yīng)激的研究,并利用C/EBP同源蛋白質(zhì)(Chop)表達基因敲除小鼠的單側(cè)輸尿管結(jié)扎(UUO)模型分析了凋亡在腎臟纖維化中所發(fā)揮的細胞機制和分子機制。我們發(fā)現(xiàn)Chop蛋白質(zhì)表達缺失后對UUO誘導的小鼠腎臟纖維化具有顯著的保護作用。由于Chop表達的缺失,在很大程度上避免了腎臟細胞的凋亡和繼發(fā)性死亡,從而減少了由死亡引起的高遷移率蛋白1 (Hmgbl)的被動釋放。與此同時,我們的研究結(jié)果還顯示Chop基因敲除可以抑制巨噬細胞主動分泌Hmgb1。由此所產(chǎn)生的效應(yīng)是小鼠腎臟組織中細胞外的Hmgb1總量下降。主動分泌或被動釋放到細胞外的Hmgbl與細胞膜表面的Toll樣受體4(TLR4)結(jié)合,激活MvD88-NF κ B信號通路,最終促進IL-1β的表達。高表達的IL-1β通過促使Tgf β/Smad2/3和Pi3k/Akt信號通路的活化,促進腎臟纖維化的形成。因此,Chop基因敲除后Hmgbl下游整條促進先纖維化形成的信號通路被抑制了。研究方法和結(jié)果前期,我們收集了慢性腎臟病終末期患者的腎臟活檢組織。通過組織病理學染色,我們觀察到終末期腎病患者的腎間質(zhì)纖維化明顯,巨噬細胞浸潤顯著增加,與此同時,CHOP RT-PCR的檢查結(jié)果顯示患者CHOP mRNA的水平明顯高于正常人。為進一步揭示CHOP在腎臟纖維化中的影響和機制,我們建立了Chop基因敲除小鼠模型。單側(cè)輸尿管結(jié)扎手術(shù)(UUO)是誘導動物腎臟纖維化的經(jīng)典模型。所以我們采用UUO手術(shù)分別誘導Chop-/-小鼠和C57BL/6小鼠的腎臟纖維化。在UUO術(shù)后14天,通過病理學的檢測,我們觀察到C57BL/6小鼠腎臟發(fā)生了嚴重的纖維化,腎間質(zhì)中有大量炎癥細胞浸潤,腎小管擴張程度及蛋白質(zhì)管型明顯,腎小管刷狀緣幾乎未見。ER stress相關(guān)因子蛋白質(zhì)及mRNA表達水平的檢測結(jié)果表明腎臟纖維化病理進程伴隨ER stress的發(fā)生。然而Chop基因敲除后可以明顯改善小鼠UUO術(shù)后的所造成的表型。形態(tài)學分析結(jié)果顯示,在相同手術(shù)過程處理下,Chop-/-小鼠的腎臟腎盂積水較C57BL/6小鼠明顯減少,腎臟皮質(zhì)厚度改變程度下降。與形態(tài)學的表型一致,Chop基因敲除后在極大程度上抑制了小鼠術(shù)后腎臟纖維化的發(fā)生,并減少了腎間質(zhì)炎癥細胞的浸潤,改善了腎小管的擴張程度,保存了腎小管刷狀緣的部分完整性。F4/80是小鼠巨噬細胞特異性表面標志,我們通過組織化學染色發(fā)現(xiàn)Chop-/-小鼠腎臟間質(zhì)中巨噬細胞的浸潤數(shù)目顯著下降。同時我們發(fā)現(xiàn)CHOP蛋白表達缺失在mRNA和蛋白質(zhì)水平均阻礙了纖維化相關(guān)指標的表達。雖然Chop處于ER stress調(diào)控通路的下游,但是可能由于正反饋機制的存在,ER stress相關(guān)蛋白的檢測結(jié)果顯示Chop基因敲除后ER stress信號通路上游因子的表達被抑制了。由ER stress誘導表達的Chop蛋白主要功能是調(diào)節(jié)細胞的程序性死亡(凋亡),但如果凋亡的細胞數(shù)目超出了腎臟自身清除能力,細胞會發(fā)生繼發(fā)性死亡。死亡后的細胞被動釋放Hmgb1。TUNEL是一項特異性高、敏感性好、表型直觀、操作簡便的檢測細胞凋亡的技術(shù)。因此我們首先采用TUNEL檢測UUO術(shù)后小鼠腎臟凋亡細胞的數(shù)目,數(shù)據(jù)分析結(jié)果顯示Chop基因敲除后,腎臟凋亡細胞的數(shù)目明顯減少。隨后我們利用免疫印跡和RT-PCR技術(shù)檢測了凋亡相關(guān)蛋白的表達,與TUNEL結(jié)果一致,Chop基因的敲除抑制凋亡的發(fā)生。乳酸脫氫酶(LDH)是細胞死亡后釋放的酶體,其含量可以指示細胞死亡的情況。腎臟溶解物中LDH的檢測結(jié)果提示Chop-/-小鼠死亡細胞數(shù)目減少,由此可以推測Chop蛋白表達的缺失阻礙了細胞的繼發(fā)性死亡。細胞外Hmgbl的產(chǎn)生方式包括被動釋放和主動分泌,通過腎臟組織Hmgbl的免疫組織化學染色和體外細胞培養(yǎng)實驗,我們發(fā)現(xiàn)兩種方式產(chǎn)生的Hmgbl在Chop-/-小鼠中均減少。同時我們證實腎病終末期患者的腎臟同樣有大量HMGB1的釋放。Toll樣受體2(TLR2)、Toll樣受體4(TLR4)和RAGE為Hmgb細胞膜上特異性受體。免疫印跡檢測三種受體UUO術(shù)后在小鼠腎臟組織中的變化,檢測結(jié)果顯示TLR2和RAGE在UUO術(shù)后表達升高,但是Chop-/-小鼠和C57BL/6小鼠腎臟中兩者的表達并無統(tǒng)計學差異。而TLR4的表達在Chop基因敲除小鼠中受到抑制。TLR4通路下游調(diào)節(jié)因子MyD88/NF κ B的表達與TLR4一致,在Chop敲除后下降。分泌到細胞外的Hmgb 1可刺激巨噬細胞分泌白介素1β(IL-1β),我們通過免疫印跡和ELISA檢測到IL-1β前體和IL-1β的表達下降。IL1β可通過直接和間接兩種方式促進纖維化的形成。我們發(fā)現(xiàn)兩條通路相關(guān)的調(diào)節(jié)因子,在Chop基因敲除后表達量均下降。結(jié)論在本篇論文中,我們以ER stress為切入點,Chop為焦點進行腎臟纖維形成機制的研究。在腎病終末期患者的腎臟組織中,我們檢測到ER stress相關(guān)蛋白表達量的增加。為進一步闡述腎臟纖維化病理機制,我們建立了小鼠腎臟纖維化模型。在研究中,我們證實Chop基因敲除后通過阻礙腎臟細胞的凋亡和繼發(fā)性壞死,抑制Hmgbl的被動釋放和主動分泌,進而抑制了Hmgbl/TLR4/MyD88/NFK B信號通路的激活。由于NFκB的活性被抑制,受其調(diào)節(jié)的IL1β的表達量下降,最終下調(diào)與纖維化形成密切相關(guān)的Tgf β/Smad2/3和Pi3k/Akt信號通路,抑制腎臟纖維化的形成。
[Abstract]:The research background of renal fibrosis is the pathological change of chronic end-stage renal disease in common, the major pathological features are glomerular sclerosis and renal interstitial fibrosis. Renal fibrosis is caused by excessive deposition of extracellular matrix, beyond the renal clearance ability, eventually leading to end-stage kidney disease (ESRD). The pathological changes of irreversible and no effective treatment for renal fibrosis, ESRD patients rely on lifelong dialysis and kidney transplant. There is plenty of evidence that activation of fibroblast and mesangial cells, renal tubular epithelial mesenchymal transition (EMT), inflammatory cells (monocytes, macrophages and T lymphocytes). Infiltration and cell apoptosis induced by activated protein Smad is an important mechanism of renal fibrosis in.TGF cells and beta downstream signal had been confirmed to promote Renal fibrosis molecular regulation mechanism of the most important, but the formation of renal fibrosis related cell activation and induce expression of TGF factor is not fully elucidated. The endoplasmic reticulum (ER) is involved in intracellular transport and protein synthesis, modification, and lipid synthesis and storage of Ca2+ cells when cells were as important. Oxidative stress, ischemia and hypoxia, endoplasmic reticulum homeostasis destruction, affect protein folding and cause endoplasmic reticulum stress (ER stress) the occurrence of persistent and cannot receive timely treatment procedures of the endoplasmic reticulum stress may induce cell death, or apoptosis. Several studies have demonstrated that apoptosis, endoplasmic reticulum stress is related to the factors affecting the body subjected to organ and tissue remodeling after injury. For example, in the process of liver fibrosis and myocardial fibrosis, endoplasmic reticulum stress was confirmed. Play a key role. However, there is no study of endoplasmic reticulum stress described in the specific regulation mechanism of renal fibrosis pathological process. At present, only Chiang et al use model of renal fibrosis in rats was confirmed by endoplasmic reticulum stress is the formation of renal fibrosis promoting factors, the degree of apoptosis and the endoplasmic reticulum stress inhibitor confirmed renal cell and is proportional to the degree of renal fibrosis. All the results above, we first studied the formation process of endoplasmic reticulum stress in patients with chronic kidney disease and renal fibrosis, and homologous protein (Chop) expression in C/EBP gene knockout mice with unilateral ureteral obstruction (UUO) model to analyze the cellular mechanisms and molecular mechanisms the apoptosis in renal fibrosis. We found that the loss of Chop protein expression on UUO induced renal fibrosis in mice significantly The protective effect of the Chop. Due to the lack of expression, largely avoided the renal cell apoptosis and secondary death, thereby reducing the caused by death of high mobility protein 1 (Hmgbl) of the passive release. At the same time, our results also showed that Chop gene knockout can inhibit the secretion of macrophage active effect Hmgb1. the resulting is the amount of Hmgb1 cells in the mouse kidney tissue decreased. Toll like receptor Hmgbl and cell membrane surface active or passive secretion release into the extracellular binding 4 (TLR4), the activation of MvD88-NF B signaling pathway, and ultimately promote the expression of IL-1 beta. The high expression of IL-1 beta promotes the activation of Tgf beta /Smad2/3 and Pi3k/Akt signaling pathway, promoting the formation of kidney fibrosis. Therefore, Chop gene knockout Hmgbl downstream signaling pathway to promote the formation of fibrosis were inhibited. The research methods and results before Period, we collected the chronic kidney disease in patients with end-stage renal biopsy. Through histopathological staining, we observed in patients with end-stage renal disease renal interstitial fibrosis, increased macrophage infiltration at the same time, CHOP RT-PCR examination showed that patients with CHOP mRNA was significantly higher than in normal people. In order to further reveal the influence of CHOP in renal fibrosis and mechanism, we established the Chop gene knockout mice model. Unilateral ureteral ligation (UUO) is a classical animal model induced by renal fibrosis. So we use the UUO operation were induced in Chop-/- mice and C57BL/6 mice kidney fibrosis. In the 14 day after UUO, through the detection of pathology. We observed that C57BL/6 mice had severe renal fibrosis, renal interstitial inflammatory cell infiltration, renal tubular dilatation and protein tube significantly, The results of detection of renal tubule brush border almost no.ER stress related factor mRNA and protein expression level showed that renal fibrosis pathological process with the ER stress. However, Chop gene knockout mice can significantly improve the postoperative UUO caused by phenotype. Morphological analysis showed that in the same surgical procedure under the treatment of Chop-/- mice kidney hydronephrosis compared with C57BL/6 mice significantly reduced renal cortical thickness changes decreased. Morphology and phenotype consistent, Chop gene knockout in largely inhibited mice after renal fibrosis occurred, and reduce the infiltration of inflammatory cells in the kidney of quality, improve the degree of renal tubular expansion, part of integrity.F4/80 saved the tubular brush border is mouse macrophage specific surface markers, we found by histochemical staining of Chop-/- mouse kidney interstitial macrophages The number of infiltrating cells decreased significantly. At the same time, we found that the lack of CHOP protein expression in mRNA and protein levels were blocked the expression indexes related to fibrosis. Although the Chop in the ER stress pathway downstream, but may be due to the existence of a positive feedback mechanism, the detection of ER stress protein showed Chop gene inhibited the expression of ER on stress signaling upstream factors in Chop protein. The main function of ER induced by stress expression is the Procedural Regulation of cell death (apoptosis), but if the number of apoptotic cells beyond the ability to remove kidney cells, the occurrence of secondary cell death. After the death of the passive release of Hmgb1.TUNEL is a high specificity and sensitivity well, the phenotype of simple and intuitive, the detection of apoptosis. So we used TUNEL cell apoptosis in mouse kidney number detection after UUO, according to the number of The analysis results show that Chop gene knockout, the number of apoptotic cells in the kidney was significantly reduced. Then we use immunohistochemistry and RT-PCR technique to detect the expression of apoptosis related protein, consistent with the results of TUNEL, Chop gene knockout of the inhibition of apoptosis. Lactate dehydrogenase (LDH) enzyme release after cell death, its content can direct cell death. Detection of renal LDH lysis results suggest that the number of dead cells in Chop-/- mice reduced, it can be speculated that the lack of Chop protein expression prevents secondary cell death. Extracellular Hmgbl production including passive and active release secretion culture experiments by immunohistochemical staining and in vitro kidney cells Hmgbl, we found two ways to produce Hmgbl were reduced in Chop-/- mice. At the same time, we confirmed that patients with end-stage kidney disease also has a large number of HM The release of.Toll GB1 like receptor 2 (TLR2), Toll like receptor 4 (TLR4) and RAGE Hmgb specific membrane receptors. Western blotting after UUO three receptors in the mouse kidney changes, test results showed that the expression of TLR2 and RAGE in UUO increased after operation, but there was no statistical difference both Chop-/- mice and C57BL/6 in mouse kidney. The expression of TLR4 in Chop gene knockout by inhibiting the.TLR4 pathway downstream factor kappa MyD88/NF B expression and TLR4 in mice, Chop knockout decreased. Secreted into the extracellular Hmgb 1 can stimulate macrophage secretion of interleukin 1 beta (we through the expression of IL-1 beta), Western blotting and ELISA detection of IL-1 beta precursor and IL-1 beta decreased.IL1 beta can promote fibrosis through direct and indirect ways. We found two regulatory factor two pathway related, in Chop gene knockout expression were Conclusion decreased. In this thesis, we use ER stress as the starting point, the study of Chop for focus formation mechanism of kidney fiber. In end-stage renal disease in the kidney tissue, we detected ER stress related protein expression increased. In order to further elaborate the pathological mechanism of renal fibrosis, we established mouse kidney fibrosis model. In this study, we confirmed that the Chop gene on apoptosis and secondary necrosis by hindering kidney cells after passive, inhibiting the release of Hmgbl and active secretion, thereby inhibiting the activation of Hmgbl/TLR4/MyD88/NFK B signaling pathway. The NF kappa B activity was inhibited by the expression regulation of IL1 beta decline, eventually downregulation of /Smad2/3 is closely related to the formation of Tgf beta and Pi3k/Akt signaling pathway and inhibit the formation of fibrosis, renal fibrosis.

【學位授予單位】：華中科技大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R692

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6 鄒文蓉;彭鵬;王瑜;;雙周CHOP方案治療彌漫大B細胞淋巴瘤的臨床研究[A];第一屆全國難治性淋巴瘤學術(shù)研討會暨第二屆全國多發(fā)性骨髓瘤學術(shù)研討會（國家級血液系統(tǒng)惡性腫瘤繼續(xù)醫(yī)學教育學習班）繼續(xù)教育集[C];2007年

7 楊建良;劉尚梅;何小慧;董梅;周生余;劉鵬;張長弓;秦燕;桂琳;楊晟;孫燕;石遠凱;;利妥昔單抗加入CHOP方案可改善療效——60例濾泡性3級淋巴瘤生存和預(yù)后因素分析[A];中國腫瘤內(nèi)科進展 中國腫瘤醫(yī)師教育（2014）[C];2014年

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9 尤安磊;張秀花;周新強;馮淑嫻;;CHOP方案聯(lián)合干擾素治療NHL22例臨床觀察[A];第十次全國淋巴瘤學術(shù)會議論文匯編[C];2007年

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