【摘要】：急性高糖是指由于某些原因?qū)е聶C體血糖水平顯著升高的現(xiàn)象,當前包括腎臟移植在內(nèi)的臨床研究發(fā)現(xiàn)圍術(shù)期高血糖水平與存在腎臟缺血再灌注患者的預后有著密切關(guān)系,但對其中的具體影響機制仍不清楚。本研究通過建立正常SD大鼠腎臟I/R急性高糖模型,評價在該模型下急性高糖對腎I/R損傷的影響和探討急性高糖對腎I/R損傷可能機制,此外對右美托嘧啶在該急性高糖模型中的影響及可能機制進行探討。第一部分急性高糖對大鼠腎缺血再灌注損傷的影響目的：探討缺血前急性高糖對正常大鼠腎I/R的影響。方法：通過建立正常SD大鼠腎I/R急性高糖模型,與單純腎I/R比較,采用形態(tài)學和功能學兩方面研究缺血前急性高糖對正常大鼠腎I/R的影響。結(jié)果：缺血前急性高糖可以加重腎缺血再灌注損傷,再灌注后24h的Cr和BUN較非高糖I/R組明顯升高。結(jié)論：急性高糖可以加重正常大鼠腎臟I/R損傷。第二部分急性高糖環(huán)境下大鼠腎缺血再灌注損傷的免疫炎癥反應(yīng)研究目的：探討缺血前急性高糖對非糖尿病大鼠腎I/R免疫炎癥反應(yīng)的影響。方法：采用分光光度法使用髓過氧化物酶(MPO)測定試劑盒測定腎組織勻漿中MPO活性。采用免疫組織化學、RT-PCR測定IL-1β, interferon-γ (IFN-γ),采用免疫組織化學、RT-PCR、Western blot法測定腎組織TLR4,TLR2,高遷移率族蛋白B1 (high-mobility group box 1,HMGB1),Cyclooxygenase 2(Cox-2)的表達。結(jié)果：急性高糖增加缺血再灌注后腎組織MPO活性,增加IL-1β, IFN-γ, TLR4, TLR2,HMGB1,Cox-2的表達水平。結(jié)論：急性高糖加重腎缺血及再灌注所引發(fā)的免疫炎性損傷。第三部分急性高糖對大鼠腎缺血再灌注損傷凋亡的影響以及右美托嘧啶預處理的影響目的：急性高糖對大鼠腎缺血再灌注損傷凋亡的影響以及右美托嘧啶預處理的影響方法：非糖尿病SD大鼠分為高糖組和正常血糖組。每組又分假手術(shù)組,缺血再灌注組,右美托嘧啶(Dexmedetomide,Dex)預處理組。采用TUNEL進行凋亡指數(shù)檢測以及Western blot法對Bax、Bcl-2蛋白表達、AKT磷酸化水平(p-AKT)進行檢測。結(jié)果：急性高糖明顯增加缺血再灌注后腎組織凋亡指數(shù),Bax, AKT磷酸化水平,降低Bcl-2表達。正常血糖環(huán)境下,Dex能明顯降低缺血再灌注所致的Bax升高水平,明顯升高缺血再灌注所致的Bcl-2, p-AKT降低水平；而在高糖環(huán)境下,Dex的這種作用被明顯減弱。結(jié)論：急性高糖加重缺血再灌注損傷腎組織的凋亡,急性高糖消除了Dex預處理對腎缺血再灌注損傷的保護作用,其機制可能與高糖環(huán)境下Dex對凋亡蛋白的調(diào)控消失,減弱了p-AKT水平的恢復有關(guān)。
[Abstract]:Acute hyperglycemia refers to the phenomenon that the blood glucose level is significantly increased due to some reasons. Current clinical studies, including kidney transplantation, have found that perioperative hyperglycemia is closely related to the prognosis of patients with renal ischemia-reperfusion. However, the specific impact on the mechanism is still unclear. In this study, a model of acute I / R hyperglycemia in kidney of normal SD rats was established to evaluate the effects of acute high glucose on renal I / R damage and to explore the possible mechanism of acute I / R injury. In addition, the effect of dextropyrimidine on the acute hyperglycemia model and its possible mechanism were discussed. Part I effects of acute hyperglycemia on renal ischemia-reperfusion injury in rats objective: to investigate the effects of acute hyperglycemia before ischemia on renal I / R in normal rats. Methods: the renal I / R acute hyperglycemic model of normal SD rats was established. The effects of acute hyperglycemia before ischemia on I / R in normal rats were studied by morphological and functional methods compared with those of simple kidney I / R. Results: acute hyperglycemia before ischemia increased renal ischemia-reperfusion injury, and Cr and BUN increased significantly 24 hours after reperfusion compared with non-hyperglycemic I / R group. Conclusion: acute hyperglycemia can aggravate renal I / R damage in normal rats. The second part is the immune inflammatory response of renal ischemia reperfusion injury in rats with acute hyperglycemia. Objective: to investigate the effect of acute high glucose concentration before ischemia on renal I / R immune inflammation in non-diabetic rats. Methods: the activity of MPO in renal homogenate was determined by using myeloperoxidase (MPO) assay kit by spectrophotometry. IL-1 尾, interferon- 緯 (IFN- 緯) and TLR4,TLR2, high mobility group protein B1 (high-mobility group box 1 HMGB1) in renal tissue were determined by immunohistochemistry, RT-PCR and RT-PCR,Western blot respectively. Expression of Cyclooxygenase 2 (Cox-2). Results: acute hyperglycemia increased the activity of MPO and the expression of IL-1 尾, IFN- 緯 and TLR4, TLR2,HMGB1,Cox-2 in renal tissue after ischemia reperfusion. Conclusion: acute hyperglycemia exacerbates the immune inflammatory injury induced by renal ischemia and reperfusion. The effect of acute high glucose on renal ischemia-reperfusion injury in rats and the effect of dextropyrimidine preconditioning objective: effects of acute high glucose on renal ischemia-reperfusion injury in rats and desmetropyrimidine preconditioning Methods: non-diabetic SD rats were divided into high glucose group and normal blood glucose group. Each group was divided into sham operation group, ischemia reperfusion group and Dexmedetomide,Dex preconditioning group. The expression of Bax,Bcl-2 protein and the level of AKT phosphorylation (p-AKT) were detected by TUNEL and Western blot. Results: acute hyperglycemia significantly increased the level of, Bax, AKT phosphorylation and decreased the expression of Bcl-2 in renal tissue after ischemia reperfusion. In normal blood glucose environment, Dex could significantly decrease the level of Bax and increase the level of Bcl-2, p-AKT induced by ischemia-reperfusion, but in high glucose environment, the effect of Dex was significantly weakened. Conclusion: acute hyperglycemia exacerbates the apoptosis of renal tissue after ischemia reperfusion injury, and the protective effect of Dex preconditioning on renal ischemia-reperfusion injury is eliminated. The mechanism may be related to the disappearance of Dex regulation on apoptotic protein in high glucose environment. Weakened the recovery of p-AKT levels related.
【學位授予單位】：武漢大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R699.2

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