【摘要】：目的：探討過(guò)度內(nèi)質(zhì)網(wǎng)應(yīng)激在大鼠慢性環(huán)孢素A (Cy-closporine A, CsA)腎毒性模型細(xì)胞凋亡中的作用機(jī)制。 方法：將Sprague-Dawley (SD)大鼠隨機(jī)分為正常對(duì)照組和慢性CsA腎毒性組,分別給予皮下注射橄欖油(1mL/kg/d,對(duì)照組)和CsA (15mg/kg/d,毒性組)1周及4周后處死大鼠。通過(guò)末端脫氧核苷酸轉(zhuǎn)移酶介導(dǎo)的dUTP缺口末端標(biāo)記測(cè)定法(TUNEL染色法)及Masson染色評(píng)估腎小管間質(zhì)纖維化和細(xì)胞凋亡：使用免疫組化學(xué)染色和免疫印跡依次檢測(cè)分子免疫球蛋白結(jié)合蛋白(Bip)、磷酸化的真核細(xì)胞翻譯起始因子2α(elF2α)、生長(zhǎng)抑制DNA損傷基因153(GADD15)、細(xì)胞凋亡相關(guān)基因caspase-12及caspase-3蛋白表達(dá)。 結(jié)果：與對(duì)照組比較,CsA注射1周觀察不到腎小管間質(zhì)纖維化和TUNEL陽(yáng)性細(xì)胞,而給予CsA注射4周大鼠表現(xiàn)為明顯的腎小管間質(zhì)纖維化[(38.9±3.3)%vs.(0.0±0.0)%,P0.01]和大量TUNEL陽(yáng)性細(xì)胞[(89±9)%vs.(7±2)%,pO.01]。在分子水平上,與對(duì)照組比較,CsA注射組Bip和caspase-12蛋白的表達(dá)1周達(dá)到高峰,4周后降至正常水平；反之,elF2α、 GADD153、caspase-3蛋白表達(dá)呈時(shí)間依賴性的增加。 結(jié)論：在慢性CsA腎毒性中,過(guò)度的內(nèi)質(zhì)網(wǎng)應(yīng)激耗盡Bip,凋亡前途徑中e1F2α、GADD153、caspase-12, caspase-3的激活導(dǎo)致腎小管上皮細(xì)胞凋亡參與腎小管間質(zhì)損傷。
[Abstract]:Aim: to investigate the mechanism of excessive endoplasmic reticulum stress (ERS) on apoptosis of chronic cyclosporine A (Cy-closporine A, CsA) nephrotoxic model in rats. Methods: Sprague-Dawley (SD) rats were randomly divided into normal control group and chronic CsA nephrotoxicity group. The rats were killed after 1 week and 4 weeks of subcutaneous injection of olive oil (1 mL / kg / d, control group) and CsA (15 mg / kg / d, toxicity group) respectively. Evaluation of tubulointerstitial fibrosis and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP Nick end labeling (TUNEL staining) and Masson staining: molecular analysis using immunohistochemical staining and Western blotting Immunoglobulin binding protein (Bip),) phosphorylation of eukaryotic cell translation initiation factor 2 偽 (elF2 偽), growth inhibition of DNA damage gene 153 (GADD15), apoptosis-related genes caspase-12 and caspase-3 protein expression. Results: compared with the control group, tubulointerstitial fibrosis and TUNEL positive cells were not observed in rats injected with CsA for 1 week, but significant renal tubulointerstitial fibrosis (38.9 鹵3.3)% vs., P 0.01) and TUNEL positive cells (89 鹵9)% vs. (7 鹵2)%, pO.01) were observed in rats treated with CsA for 4 weeks. At the molecular level, the expression of Bip and caspase-12 protein in CsA injection group reached the peak at 1 week and decreased to normal level after 4 weeks, whereas the expression of elF2 偽 and GADD153,caspase-3 protein increased in a time dependent manner. Conclusion: in chronic CsA nephrotoxicity, the activation of e1F2 偽 and GADD153,caspase-12, caspase-3 in the preapoptotic pathway of Bip, induced by excessive endoplasmic reticulum stress leads to the apoptosis of renal tubular epithelial cells involved in tubulointerstitial injury.
【學(xué)位授予單位】：延邊大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R692

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