發(fā)布時(shí)間：2018-09-03 09:45

【摘要】：急性腎損傷（acute kidney injury,AKI）是由多種疾病引起的一種常見(jiàn)的臨床綜合征，是指由導(dǎo)致腎臟結(jié)構(gòu)或功能變化的損傷引起的腎臟功能突然惡化。缺血再灌注損傷（ischemia reperfusion injury, IRI）是導(dǎo)致急性腎損傷的主要原因之一，具有較高的發(fā)病率和死亡率，伴隨著一系列的細(xì)胞事件發(fā)生，包括細(xì)胞壞死、細(xì)胞凋亡、炎癥細(xì)胞的浸潤(rùn)和活性介質(zhì)的釋放，從而導(dǎo)致組織損傷。 內(nèi)質(zhì)網(wǎng)（endoplasmic reticulum，ER）是真核細(xì)胞中具有重要作用的細(xì)胞器，它的主要作用是參與蛋白質(zhì)的合成及轉(zhuǎn)運(yùn)，各種蛋白的糖基化修飾以及鈣離子的儲(chǔ)存與分布等。細(xì)胞在多種理化因素（缺氧、饑餓、鈣離子平衡失調(diào)、化學(xué)毒物等）的刺激下，內(nèi)質(zhì)網(wǎng)腔內(nèi)會(huì)出現(xiàn)蛋白質(zhì)的錯(cuò)誤折疊及未折疊蛋白質(zhì)的聚集等現(xiàn)象，從而引起內(nèi)質(zhì)網(wǎng)功能紊亂，這種狀態(tài)稱(chēng)為內(nèi)質(zhì)網(wǎng)應(yīng)激（endoplasmic reticulum stress，ERS）。 腎臟缺血再灌注損傷是由于腎臟供血障礙引起的一種常見(jiàn)的應(yīng)激性疾病，20世紀(jì)70年代由Glaumann等提出在恢復(fù)缺血后的腎臟的血液供應(yīng)，可加重原有的單純由缺血所造成的損傷，并且指出缺血再灌注損傷的發(fā)病基礎(chǔ)是局部能量代謝障礙，發(fā)病的重要環(huán)節(jié)則是自由基產(chǎn)生和鈣超載。已經(jīng)證實(shí)，腎臟缺血再灌注損傷與內(nèi)質(zhì)網(wǎng)應(yīng)激密切相關(guān)。在此過(guò)程中，組織的缺血缺氧、葡萄糖/營(yíng)養(yǎng)物質(zhì)匱乏、ATP耗竭、大量自由基的產(chǎn)生及鈣離子穩(wěn)態(tài)破壞等均可引起內(nèi)質(zhì)網(wǎng)功能障礙，觸發(fā)內(nèi)質(zhì)網(wǎng)應(yīng)激。過(guò)度內(nèi)質(zhì)網(wǎng)應(yīng)激通過(guò)破壞鈣離子穩(wěn)態(tài)、誘導(dǎo)細(xì)胞凋亡而加重缺血再灌注損傷，但其具體的機(jī)制一直沒(méi)有得到詳細(xì)闡述。最新研究發(fā)現(xiàn)，腎臟缺血再灌注損傷模型中，內(nèi)質(zhì)網(wǎng)源性轉(zhuǎn)錄因子CHOP，又名生長(zhǎng)抑制DNA損傷基因153抗原（growth arrest and DNAdamage inducible153，GADDl53）表達(dá)升高，同時(shí)caspase-11的表達(dá)升高，造成腎臟功能的損害。據(jù)此，我們推測(cè)CHOP介導(dǎo)細(xì)胞凋亡在腎臟缺血再灌注損傷中起到重要作用。 本課題通過(guò)對(duì)野生型小鼠和CHOP敲除小鼠建立腎臟缺血再灌注損傷模型，探明CHOP在腎臟缺血再灌注損傷中的具體作用和機(jī)制，并進(jìn)一步在體外實(shí)驗(yàn)中培養(yǎng)人腎小管上皮細(xì)胞（HK-2）和人臍靜脈內(nèi)皮細(xì)胞（HUVEC）并建立缺氧復(fù)氧損傷模型，驗(yàn)證CHOP的重要作用及其分子機(jī)制，為闡明急性缺血性腎損傷發(fā)生機(jī)制以及尋找新的治療靶點(diǎn)提供科學(xué)依據(jù)。 1.實(shí)驗(yàn)方法 1.1實(shí)驗(yàn)動(dòng)物 CHOP敲除小鼠由美國(guó)Jackson實(shí)驗(yàn)室引進(jìn)。體重22~26克的成年雄性野生型小鼠和CHOP敲除小鼠應(yīng)用于本次試驗(yàn)。實(shí)驗(yàn)動(dòng)物給于12小時(shí)晝夜交替飼養(yǎng)和自由的飲水、飲食。 1.2腎臟缺血再灌注損傷模型 實(shí)驗(yàn)動(dòng)物經(jīng)戊巴比妥鈉（60毫克/公斤）腹腔注射麻醉后，放置于安裝有控溫儀器的手術(shù)臺(tái)上，整個(gè)實(shí)驗(yàn)過(guò)程中控制體溫在36℃左右。取腹正中切口，切除右腎，用防損傷微血管夾夾閉左側(cè)腎臟動(dòng)、靜脈25分鐘。假手術(shù)組只分離腎蒂，切除右腎，未夾閉左側(cè)腎動(dòng)靜脈。實(shí)驗(yàn)動(dòng)物在缺血再灌注24小時(shí)后經(jīng)腹主動(dòng)脈穿刺取血及留取腎臟組織做進(jìn)一步檢查分析。 1.3骨髓移植 供者、受者均選擇8~10周的雄鼠，受者經(jīng)鈷源60照射2次，總劑量10.5Gy，間隔4小時(shí)。在照射后2小時(shí)，由供者提取骨髓細(xì)胞按1×107個(gè)/只尾靜脈注射給受者。在骨髓移植后30天建立腎臟缺血再灌注損傷模型。 1.4細(xì)胞培養(yǎng)及缺氧復(fù)氧（HR）模型 人腎小管上皮細(xì)胞（HK-2）和人臍靜脈內(nèi)皮細(xì)胞（HUVEC）培養(yǎng)在含有10%胎牛血清的DMEM中，放置于37°C，5%CO2的培養(yǎng)箱內(nèi)。實(shí)驗(yàn)鋪盤(pán)于6孔板內(nèi)，按照5×105個(gè)細(xì)胞/孔。根據(jù)實(shí)驗(yàn)方案，細(xì)胞放置于正常環(huán)境（5%CO2,21%O2和74%N2）和缺氧環(huán)境（5%CO2，1%O2和94%N2）。 1.5siRNA干擾的構(gòu)建 CHOP的siRNA是由美國(guó)英杰生物技術(shù)公司合成、純化、退火。siRNA合成的具體序列為：GCUAGCUGAAGAGAAUGAATT；UUCAUUCUCUUCAGCUAGCTT。HK-2細(xì)胞和HUVECs按照80nM的質(zhì)粒濃度運(yùn)用Lipofectamin2000進(jìn)行轉(zhuǎn)染干擾。 2.實(shí)驗(yàn)結(jié)果 2.1CHOP在小鼠腎臟缺血再灌注損傷中介導(dǎo)細(xì)胞凋亡 2.1.1腎臟IR后CHOP、cleaved caspase-3蛋白表達(dá)情況 與對(duì)照組相比，腎臟IR后3小時(shí)開(kāi)始CHOP、cleaved caspase-3蛋白表達(dá)升高，于再灌注6小時(shí)達(dá)高峰，并持續(xù)至24小時(shí)，均明顯高于對(duì)照組（p0.05）。 2.1.2CHOP敲除后cleaved caspase-3蛋白表達(dá)情況及生存率、腎功、病理的改變 cleaved caspase-3蛋白表達(dá)變化：CHOP敲除小鼠IR后6小時(shí)的cleaved caspase-3蛋白表達(dá)較野生型小鼠降低（p0.05）。 生存率的比較：CHOP敲除小鼠IR后生存率（80%）較野生型小鼠（0%）顯著提高（p0.05）。 腎功的比較：CHOP敲除小鼠IR后24小時(shí)血肌酐、血尿素氮均較野生型小鼠顯著降低（p0.05）。 病理的比較：CHOP敲除小鼠IR后24小時(shí)病理改變均較野生型小鼠顯著減輕（p0.05）。 2.1.3CHOP敲除通過(guò)影響腎臟微循環(huán)灌注減輕IR損傷 與野生型小鼠IR后相比，CHOP敲除能顯著改善缺血后腎臟早期的微循環(huán)灌注，從而減輕小鼠腎臟缺血再灌注損傷。 2.2骨髓移植證實(shí)腎臟固有細(xì)胞而不是骨髓來(lái)源的免疫細(xì)胞中CHOP介導(dǎo)IR中的細(xì)胞凋亡 2.2.1四組骨髓移植小鼠IR后生存率的改變 生存率的比較：四組骨髓移植小鼠IR后觀察7天，骨髓移植WT→WT小鼠生存率（0%）與骨髓移植CHOP-/-→WT小鼠生存率（0%）相比，，無(wú)統(tǒng)計(jì)學(xué)差異（p0.05）；骨髓移植WT→CHOP-/-小鼠生存率（80%）與骨髓移植CHOP-/-→CHOP-/-小鼠生存率（70%）相比，無(wú)統(tǒng)計(jì)學(xué)差異（p0.05）。 2.2.2四組骨髓移植小鼠IR后腎功的改變 腎功的比較：骨髓移植WT→WT小鼠與骨髓移植CHOP-/-→WT小鼠相比，IR后24小時(shí)的血肌酐、血尿素氮無(wú)統(tǒng)計(jì)學(xué)差異（p0.05）；骨髓移植WT→CHOP-/-小鼠與骨髓移植CHOP-/-→CHOP-/-小鼠，IR后24小時(shí)的血肌酐、血尿素氮無(wú)統(tǒng)計(jì)學(xué)差異（p0.05）。 2.2.3四組骨髓移植小鼠IR后病理的改變 病理的比較：骨髓移植WT→WT小鼠與骨髓移植CHOP-/-→WT小鼠相比，IR后24小時(shí)的病理改變無(wú)統(tǒng)計(jì)學(xué)差異（p0.05）；骨髓移植WT→CHOP-/-小鼠與骨髓移植CHOP-/-→CHOP-/-小鼠，IR后24小時(shí)的病理改變無(wú)統(tǒng)計(jì)學(xué)差異（p0.05）。 2.3腎小管上皮細(xì)胞及內(nèi)皮細(xì)胞中CHOP介導(dǎo)細(xì)胞凋亡 2.3.1缺氧復(fù)氧引起腎小管上皮細(xì)胞損傷 LDH水平：與對(duì)照組相比，細(xì)胞上清LDH水平于HR后6小時(shí)增加，持續(xù)增加至復(fù)氧24小時(shí)（p0.05）。 CHOP蛋白表達(dá)：與對(duì)照組相比，HR后6小時(shí)升高，持續(xù)增加至24小時(shí)（p0.05）。 cleaved caspase-3蛋白表達(dá)：與對(duì)照組相比，HR后6小時(shí)升高，持續(xù)增加至24小時(shí)（p0.05）。 2.3.2缺氧復(fù)氧引起內(nèi)皮細(xì)胞損傷 LDH水平：與對(duì)照組相比，細(xì)胞上清LDH水平于HR后6小時(shí)增加，持續(xù)至復(fù)氧24小時(shí)未見(jiàn)明顯下降（p0.05）。 CHOP蛋白表達(dá)：與對(duì)照組相比，HR后6小時(shí)升高，持續(xù)至復(fù)氧24小時(shí)未見(jiàn)明顯下降（p0.05）。 cleaved caspase-3蛋白表達(dá)：與對(duì)照組相比，HR后6小時(shí)升高，持續(xù)至復(fù)氧24小時(shí)未見(jiàn)明顯下降（p0.05）。 2.3.3CHOP基因沉默顯著減輕HR誘導(dǎo)的腎小管上皮細(xì)胞損傷 LDH水平：與HR24小時(shí)組比較，CHOP siRNA顯著減輕HR后腎小管上皮細(xì)胞損傷，細(xì)胞培養(yǎng)上清中LDH水平明顯下降（p0.05）。 CHOP siRNA顯著抑制HR誘導(dǎo)的腎小管上皮細(xì)胞CHOP蛋白的表達(dá)（p0.05）。 CHOP基因沉默可顯著抑制HR后24小時(shí)腎小管上皮細(xì)胞cleaved caspase-3的蛋白的表達(dá)（p0.05）。 2.3.4CHOP基因沉默顯著減輕HR誘導(dǎo)的內(nèi)皮細(xì)胞損傷 LDH水平：與HR6小時(shí)組比較，CHOP siRNA顯著減輕HR內(nèi)皮細(xì)胞損傷，細(xì)胞培養(yǎng)上清中LDH水平明顯下降（p0.05）。 CHOPsiRNA顯著抑制HR誘導(dǎo)的內(nèi)皮細(xì)胞CHOP蛋白的表達(dá)（p0.05）。 CHOP基因沉默可顯著抑制HR后6小時(shí)內(nèi)皮細(xì)胞cleaved caspase-3蛋白的表達(dá)（p0.05）。 3.結(jié)論 腎臟固有細(xì)胞中的CHOP的激活在介導(dǎo)腎臟IR損傷中的細(xì)胞凋亡、腎臟功能損害起到重要作用，而敲除固有細(xì)胞中的CHOP后細(xì)胞凋亡減少，腎臟功能得到一定的保護(hù)。
[Abstract]:Acute kidney injury (AKI) is a common clinical syndrome caused by a variety of diseases. It refers to the sudden deterioration of renal function caused by the damage of kidney structure or function. Ischemia reperfusion injury (IRI) is one of the main causes of acute kidney injury and has a high incidence. Morbidity and mortality are accompanied by a series of cellular events, including cell necrosis, apoptosis, infiltration of inflammatory cells and release of active mediators, leading to tissue damage.
Endoplasmic reticulum (ER) is an important organelle in eukaryotic cells. It plays an important role in the synthesis and transport of proteins, glycosylation modification of proteins and the storage and distribution of calcium ions. Endoplasmic reticulum stress (ERS) is a state of endoplasmic reticulum stress (ERS) in which misfolded and unfolded proteins accumulate in the endoplasmic reticulum.
Renal ischemia-reperfusion injury is a common stress disease caused by renal dysfunction of blood supply. Glaumann et al. proposed in the 1970s that restoring the blood supply of the kidney after ischemia could aggravate the original injury caused by ischemia alone, and pointed out that the pathogenesis of ischemia-reperfusion injury is based on the impairment of local energy metabolism. It has been proved that renal ischemia-reperfusion injury is closely related to endoplasmic reticulum stress. In this process, tissue ischemia-hypoxia, glucose/nutrient deficiency, ATP depletion, large amount of free radicals production and calcium homeostasis damage can cause endoplasmic reticulum dysfunction, triggering. Endoplasmic reticulum stress. Excessive endoplasmic reticulum stress aggravates ischemia-reperfusion injury by destroying calcium homeostasis and inducing apoptosis, but its specific mechanism has not been elaborated in detail. The expression of owth arrest and DNA damage inducible 153 (GADDl53) was elevated, while the expression of caspase-11 was elevated, resulting in damage to renal function.
In this study, we established a renal ischemia-reperfusion injury model in wild type mice and CHOP knockout mice to explore the specific role and mechanism of CHOP in renal ischemia-reperfusion injury, and further cultured human renal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVEC) in vitro and established a hypoxia-reoxygenation injury model. The important role of CHOP and its molecular mechanism provide scientific basis for elucidating the pathogenesis of acute ischemic renal injury and searching for new therapeutic targets.
1. experimental method
1.1 experimental animals
CHOP knockout mice were imported from Jackson Laboratory of USA. Adult male wild type mice weighing 22-26 g and CHOP knockout mice were used in this experiment. The experimental animals were fed day and night for 12 hours and fed free water and diet.
1.2 renal ischemia-reperfusion injury model
After anesthesia with sodium pentobarbital (60 mg/kg), the animals were placed on the operating table equipped with a thermostat. During the whole experiment, the body temperature was controlled at about 36 C. The right kidney was removed through a median abdominal incision, and the left renal artery and vein were clamped with a protective microvascular clip for 25 minutes. Left renal artery and vein were not clamped. Blood samples were taken from abdominal aorta and kidney tissues were taken for further examination 24 hours after ischemia and reperfusion.
1.3 bone marrow transplantation
The recipients were irradiated with cobalt 60 twice at a total dose of 10.5 Gy at intervals of 4 hours. Two hours after irradiation, bone marrow cells were extracted from the donor and injected into the recipient by 1 *107 cells per caudal vein. A renal ischemia-reperfusion injury model was established 30 days after bone marrow transplantation.
1.4 cell culture and anoxia reoxygenation (HR) model
Human renal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVEC) were cultured in DMEMs containing 10% fetal bovine serum and placed in incubators with 37 C and 5% CO2. The cells were placed in 6-well plates with 5 105 cells/pores. According to the experimental scheme, the cells were placed in normal (5% CO2, 21% O2 and 74% N2) and hypoxic (5% CO2, 1% O2 and 94% N2).
Construction of 1.5siRNA interference
The siRNA of CHOP was synthesized, purified and annealed by Yingjie Biotechnology Company, USA. The specific sequence of siRNA synthesis was GCUAGGAAUGAATT, UUCUCUUCAGCUAGCTT.HK-2 cells and HUVECs were transfected with Lipofectamin 2000 at 80nM plasmid concentration.
2. experimental results
2.1CHOP mediates apoptosis in renal ischemia-reperfusion injury in mice
Expression of CHOP and cleaved caspase-3 protein in 2.1.1 kidneys after IR
Compared with the control group, the expression of cleaved caspase-3 protein increased at the beginning of CHOP 3 hours after IR, reached the peak at 6 hours after reperfusion, and lasted for 24 hours, which was significantly higher than that of the control group (p0.05).
Cleaved caspase-3 protein expression and survival rate, renal function and pathological changes after 2.1.2CHOP knockout
Changes of cleaved caspase-3 protein expression: The expression of cleaved caspase-3 protein in CHOP knockout mice 6 hours after IR was lower than that in wild type mice (p0.05).
Survival rate: the survival rate of CHOP knockout mice after IR (80%) was significantly higher than that of wild type mice (0%) (P0.05).
Comparison of renal function: CHOP knockout mice 24 hours after IR serum creatinine, blood urea nitrogen were significantly lower than wild type mice (p0.05).
Pathological comparison: the pathological changes of CHOP knockout mice were significantly reduced at 24 hours after IR (P0.05).
2.1.3CHOP knockout reduces IR damage by affecting renal microcirculation perfusion
CHOP knockout significantly improved the early microcirculatory perfusion of ischemic kidneys, thereby reducing the renal ischemia-reperfusion injury in mice compared with wild-type mice after IR.
2.2 Bone marrow transplantation confirms that CHOP mediates apoptosis in IR in renal innate cells rather than in bone marrow-derived immune cells
Changes in survival rate after IR in 2.2.1 four groups of bone marrow transplant mice
Survival rate of four groups of bone marrow transplantation mice after IR observation 7 days, bone marrow transplantation WT WT mice survival rate (0%) and bone marrow transplantation CHOP -/- WT mice survival rate (0%) compared with no significant difference (p0.05); bone marrow transplantation WT CHOP -/- mice survival rate (80%) and bone marrow transplantation CHOP -/- CHOP /- mice survival rate (70%) compared with no significant difference. Difference (P0.05).
Changes in renal function after 2.2.2 IR in four groups of bone marrow transplant mice
Comparison of renal function: There was no significant difference in serum creatinine and blood urea nitrogen between bone marrow transplanted WT WT mice and bone marrow transplanted CHOP -/- WT mice 24 hours after IR (p0.05); there was no significant difference in serum creatinine and blood urea nitrogen between bone marrow transplanted WT CHOP -/- mice and bone marrow transplanted CHOP -/ CHOP -/- mice 24 hours after IR (p0.05).
Pathological changes of 2.2.3 four groups of bone marrow transplantation mice after IR
Pathological comparison: BMT WT WT mice and BMT CHOP -/- WT mice had no significant difference in pathological changes 24 hours after IR (p0.05); BMT WT CHOP -/- mice and BMT CHOP -/- mice, there was no significant difference in pathological changes 24 hours after IR (p0.05).
2.3, CHOP mediated apoptosis in renal tubular epithelial cells and endothelial cells.
Injury of renal tubular epithelial cells induced by 2.3.1 hypoxia reoxygenation
LDH level: Compared with the control group, the level of LDH in cell supernatant increased 6 hours after HR and continued to increase to 24 hours after reoxygenation (p0.05).
CHOP protein expression: compared with the control group, HR increased after 6 hours, and increased to 24 hours (P0.05).
Cleaved caspase-3 protein expression: compared with the control group, 6 hours after HR increased, continued to increase to 24 hours (p0.05).
Endothelial cell injury induced by 2.3.2 hypoxia reoxygenation
LDH level: Compared with the control group, the level of LDH in cell supernatant increased 6 hours after HR and did not decrease significantly until 24 hours after reoxygenation (p0.05).
CHOP protein expression: Compared with the control group, HR increased at 6 hours and remained unchanged until 24 hours after reoxygenation (p0.05).
Cleaved caspase-3 protein expression: compared with the control group, HR increased at 6 hours and did not decrease significantly until 24 hours after reoxygenation (p0.05).
2.3.3CHOP gene silencing significantly alleviated HR induced renal tubular epithelial cell injury
LDH level: Compared with HR 24 hours group, CHOP siRNA significantly reduced the injury of renal tubular epithelial cells after HR, and the LDH level in cell culture supernatant decreased significantly (p0.05).
CHOP siRNA significantly inhibited the expression of CHOP protein in renal tubular epithelial cells induced by HR (P0.05).
CHOP gene silencing significantly inhibited the expression of cleaved caspase-3 protein in renal tubular epithelial cells 24 hours after HR (p0.05).
2.3.4CHOP gene silencing significantly alleviated endothelial cell injury induced by HR
LDH level: Compared with HR6-hour group, CHOP siRNA significantly reduced the injury of HR endothelial cells, and LDH level in cell culture supernatant decreased significantly (p0.05).
CHOPsiRNA significantly inhibited HR induced CHOP protein expression in endothelial cells (P0.05).
CHOP gene silencing significantly inhibited the expression of cleaved caspase-3 protein in endothelial cells 6 hours after HR (P0.05).
3. conclusion
The activation of CHOP in intrinsic cells of kidney plays an important role in mediating apoptosis and impairment of renal function in IR injury of kidney.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R692.5

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