本文選題：糖尿病腎病 + 白藜蘆醇��； 參考：《吉林大學》2014年博士論文

【摘要】：糖尿病腎病(diabetic nephropathy, DN）是糖尿病最重要的微血管并發(fā)癥之一。據(jù)發(fā)達國家統(tǒng)計資料表明，DN已躍升為終末期腎病的首位病因。近年來我國糖尿病患者人數(shù)日益增多，DN已成為我國導(dǎo)致慢性腎功能衰竭的重要原因之一。目前認為DN與糖代謝紊亂、血流動力學異常、氧化應(yīng)激、糖基化終末產(chǎn)物堆積、細胞因子異常表達等多種因素有關(guān)。其中炎癥因子與氧化應(yīng)激、免疫反應(yīng)相互作用是導(dǎo)致糖尿病腎損害，造成系膜外基質(zhì)積聚的重要原因。白藜蘆醇具有抗炎、抗氧化、抗癌、心臟保護等作用，作用機理涉及包括環(huán)氧酶、脂氧酶、蛋白激酶B(protein kinase B，PKB/Akt)、絲裂原活化蛋白激酶家族、去乙�；傅榷鄠�信號傳導(dǎo)通路。最新的研究發(fā)現(xiàn)白藜蘆醇還具有降低血糖，改善胰島素抵抗，調(diào)節(jié)異常脂代謝，減少炎癥因子分泌和表達等作用。Akt能夠通過對葡萄糖轉(zhuǎn)運、糖原合成、糖酵解和糖異生的調(diào)節(jié)及相關(guān)基因的突變、沉默、敲除影響葡萄糖的代謝及糖尿病的發(fā)生和發(fā)展,在糖尿病血管并發(fā)癥產(chǎn)生、發(fā)展的病理生理過程中也起到關(guān)鍵作用。核因子κB (nuclear factor-κB， NF-κB)是參與氧化應(yīng)激、炎性反應(yīng)的關(guān)鍵因子之一,與血管內(nèi)皮細胞損傷、組織細胞凋亡等糖尿病血管并發(fā)癥的多個病理生理過程相關(guān)。多項研究提示白藜蘆醇可能成為治療糖尿病及其并發(fā)癥的新型藥物，而這些作用的發(fā)揮可能與該藥可以對細胞內(nèi)多個信號轉(zhuǎn)導(dǎo)通路產(chǎn)生影響有關(guān)，其中Akt、NF-κB可能發(fā)揮了重要作用。本研究旨在探討白藜蘆醇對于糖尿病所致的腎臟炎癥與系膜細胞增殖的保護作用及相關(guān)機制。 在體外實驗當中，我們應(yīng)用高糖模擬糖尿病患者的體內(nèi)環(huán)境，應(yīng)用Western blot、ELISA以及BRDU、CCK8試劑盒檢測炎癥因子、細胞通路蛋白及細胞增殖情況。通過觀察不同濃度、不同處理時間點白藜蘆醇對高糖環(huán)境下原代大鼠系膜細胞對人纖溶酶原激活物抑制劑-1（plasminogenactivator inhibitor-1，PAI-1）表達和Akt活性的影響確定白藜蘆醇的有效作用濃度和有效作用時間。應(yīng)用白藜蘆醇及兩種Akt活性抑制劑，作用于Akt上游磷脂酰肌醇-3激酶（PI3K）的LY294002和直接作用于Akt的MK2206，處理高糖環(huán)境下原代大鼠系膜細胞。結(jié)果顯示，與正常對照組相比，高糖處理組中NF-κB、PAI-1表達明顯增加(P0.05)；與高糖處理組相比，白藜蘆醇和Akt活性抑制劑處理組NF-κB、PAI-1表達明顯下降(P0.05)。提示處于NF-κB下游的PAI-1表達變化可能與Akt/NF-κB通路有關(guān)。檢測應(yīng)用白藜蘆醇及Akt活性抑制劑處理的原代大鼠系膜細胞，在高糖刺激24小時后細胞增殖及同期細胞上清液當中層粘連蛋白（fibronetic,FN）表達情況。結(jié)果顯示，與正常對照組相比，高糖處理組細胞增殖明顯增強(P0.05)，白藜蘆醇和Akt活性抑制劑處理組細胞增殖較高糖處理組細胞增殖水平下降(P0.05)。與正常對照組相比，高糖處理組FN表達明顯增加(P0.05)，白藜蘆醇和Akt活性抑制劑處理組FN表達水平較高糖處理組明顯下降(P0.05)。提示白藜蘆醇對高糖刺激下原代大鼠系膜細胞增殖及FN分泌表達的影響可能與抑制Akt活性有關(guān)。 在動物實驗當中，我們應(yīng)用小劑量多次注射鏈脲佐菌素的方法建立1型糖尿病小鼠動物模型。并在模型建立成功后，給予糖尿病組小鼠白藜蘆醇(10mg/kg/d)灌胃，正常對照組給予相同體積生理鹽水灌胃，12周后處死小鼠，收集血液、尿液及腎臟標本。我們應(yīng)用Real-time PCR、Western blot、PAS染色及免疫組織化學法檢測腎臟功能學、形態(tài)學及生物化學指標。結(jié)果顯示，在功能學方面，與正常對照組小鼠相比，糖尿病組與白藜蘆醇治療組小鼠空腹血糖、尿素氮、肌酐顯著升高(P0.05)，治療組在應(yīng)用白藜蘆醇干預(yù)12周后血糖、尿素氮、肌酐有所下降，但差異沒有顯著性(P0.05)。與正常對照組小鼠相比，糖尿病組與白藜蘆醇治療組小鼠的尿白蛋白與尿肌酐比值（albumin/creatinine ratio, ACR）顯著升高(P0.05)；與糖尿病組相比，白藜蘆醇治療組ACR顯著降低(P0.05)。在形態(tài)學方面，白藜蘆醇治療組較糖尿病組系膜細胞增生，系膜外基質(zhì)增多等病理改變顯著減輕。在分子生物學方面，反映Akt活性的p-Akt/Akt、NF-κB表達在糖尿病組和白藜蘆醇治療組均顯著高于正常對照組(P0.05)。與糖尿病組相比，上述指標在白藜蘆醇治療組明顯下降。免疫組織化學顯示上述蛋白在腎間質(zhì)、腎小管及腎小球均有表達，變化趨勢與Western blot檢測結(jié)果一致。炎癥因子PAI-1、細胞間粘附分子-1（intercellular adhesionmolecule-1，ICAM-1）蛋白表達在糖尿病組與白藜蘆醇治療組均顯著高于正常對照組(P0.05)。與糖尿病組相比，，上述指標在白藜蘆醇治療組明顯下降(P0.05)。免疫組織化學顯示PAI-1蛋白在腎間質(zhì)、腎小管及腎小球均有表達，變化趨勢與Western blot檢測結(jié)果一致。在細胞增殖方面，與正常對照組相比，糖尿病組增殖細胞核抗原（PCNA）mRNA水平明顯增加(P0.05)，白藜蘆醇治療組PCNA mRNA水平較糖尿病組明顯下降(P0.05)。免疫組化結(jié)果顯示，糖尿病組小鼠腎臟每單位面積當中PCNA陽性細胞明顯多于正常對照組(P0.05)，而經(jīng)過白藜蘆醇治療則明顯減少了小鼠腎臟每單位面積當中的PCNA陽性細胞數(shù)目(P0.05)。 綜上所述，本研究證實了： （1）白藜蘆醇能夠明顯減少高糖刺激下細胞因子NF-κB、PAI-1的過表達，降低細胞增殖水平。說明白藜蘆醇能夠降低高糖環(huán)境下原代大鼠系膜細胞的炎癥反應(yīng)和細胞增殖。 （2）白藜蘆醇和Akt活性抑制劑均能夠有效降低原代大鼠系膜細胞在高糖刺激下異常增高的Akt活性，減少細胞因子NF-κB、PAI-1的過表達。說明白藜蘆醇與Akt/NF-κB通路關(guān)系密切。 (3)在1型糖尿病小鼠模型成功建立后，連續(xù)應(yīng)用白藜蘆醇干預(yù)12周，白藜蘆醇處理組小鼠ACR下降，PAI-1、ICAM-1表達減少，病理改變減輕，腎組織PCNA陽性細胞數(shù)目下降。說明白藜蘆醇可以顯著減輕DN所致的蛋白尿、炎癥和系膜細胞增生。 (4)白藜蘆醇對于糖尿病腎病的保護作用可能是通過抑制Akt活性，下調(diào)NF-κB蛋白表達，進而減輕炎癥反應(yīng)、抑制系膜細胞增殖來實現(xiàn)的。 本研究的主要創(chuàng)新點為： (1)首次在動物實驗當中證實了白藜蘆醇可以通過Akt/NF-κB路徑抑制腎小球系膜細胞增殖。 (2)通過體內(nèi)與體外兩方面實驗闡明了白藜蘆醇以及Akt活性抑制劑與DN中炎癥介質(zhì)PAI-1、ICAM-1的關(guān)系,并提出上述影響可能與Akt/NF-κB通路有關(guān)。
[Abstract]:Diabetic nephropathy (DN) is one of the most important microvascular complications of diabetes. According to the statistics of developed countries, DN has jumped to the first cause of end-stage renal disease. In recent years, the number of diabetic patients in China is increasing, and DN has become one of the important causes of slow renal failure in China. At present, DN is considered to be a major cause of chronic renal failure. It is related to many factors such as disorder of sugar metabolism, abnormal hemodynamics, oxidative stress, accumulation of end products of glycosylation, abnormal expression of cytokine and other factors. The interaction of inflammatory factors and oxidative stress and immune response is the main cause of diabetic renal damage, which causes the accumulation of extracellular matrix. Resveratrol has anti-inflammatory, antioxidant and anti-cancer. Cardiac protection and so on, the mechanism of action involves multiple signal transduction pathways including epoxidase, lipoxygenase, protein kinase B (protein kinase B, PKB/Akt), mitogen activated protein kinase family, deacetylase and so on. The latest research has found that resveratrol also reduces blood sugar, improves insulin resistance, regulates abnormal lipid metabolism, and reduces inflammation. .Akt can play a key role in the production and development of diabetic vascular complications and development. Nuclear factor kappa B (n) can also play a key role in the development of diabetic vascular complications and development of diabetes by the transfer of glucose, glycogen synthesis, glycolysis and sugar isogenesis and the mutation of related genes. Uclear factor- kappa B, NF- kappa B) is one of the key factors involved in oxidative stress and inflammatory response. It is related to multiple pathophysiological processes of vascular endothelial cell injury, tissue cell apoptosis and other diabetic vascular complications. Many studies suggest that resveratrol may be a new drug for the treatment of diabetes and its complications. Akt, NF- kappa B may play an important role in the effects of the drug on multiple signal transduction pathways in cells. This study aims to explore the protective effect of resveratrol on renal inflammation and mesangial cell proliferation induced by diabetes and its mechanism.
In vitro experiments, we used high glucose to simulate the internal environment of diabetic patients. We used Western blot, ELISA and BRDU, CCK8 kit to detect the inflammatory factors, cell pathway proteins and cell proliferation. By observing different concentrations and different treatment time points, resveratrol was used for the human fibrinolytic enzyme in the primary rat mesangial cells under high glucose environment. The effect of the expression of the original activator inhibitor -1 (plasminogenactivator inhibitor-1, PAI-1) and the activity of Akt to determine the effective concentration and effective time of resveratrol. The use of resveratrol and two kinds of Akt activity inhibitors, the LY294002 of the phosphatidyl inositol -3 kinase (PI3K) in the upstream of Akt and the direct action on Akt MK2206, and the treatment of high sugar Compared with the normal control group, the expression of NF- kappa B and PAI-1 increased significantly (P0.05), and the expression of NF- kappa B and PAI-1 in the treatment group of resveratrol and Akt activity decreased significantly compared with the high glucose treatment group, suggesting that the expression of PAI-1 expression in the lower reaches of NF- kappa B may be associated with those of NF- kappa B downstream. Primary rat mesangial cells treated with resveratrol and Akt activity inhibitor were used to detect the proliferation of cells and the expression of fibronetic (FN) in the cell supernatant after 24 hours of high glucose stimulation. The results showed that the cell proliferation of the high glucose treatment group was significantly enhanced (P0.05), resveratrol, compared with the normal control group (P0.05). Compared with the normal control group, the expression of FN in the high glucose treatment group was significantly increased (P0.05), and the expression level of FN in the resveratrol and Akt active inhibitor treated group was significantly lower than that in the high glucose treatment group (P0.05). The results suggested that resveratrol was stimulated by high glucose in the original generation, compared with the normal control group (P0.05). The influence of mesangial cell proliferation and FN secretion expression may be related to inhibition of Akt activity.
In animal experiments, we used a small dose of streptozotocin to establish a model of type 1 diabetic mice. After the establishment of the model, the diabetic mice were fed with resveratrol (10mg/kg/d), and the normal control group was given the same volume of saline. After 12 weeks, the mice were killed and the blood, urine and kidney were collected. We used Real-time PCR, Western blot, PAS staining and immunohistochemical staining to detect renal function, morphology and biochemical indexes. The results showed that the diabetic group and the resveratrol group were significantly higher than the normal control group (P0.05) in the diabetic group and the resveratrol treatment group (P0.05), and the treatment group was significantly higher than the normal control group (P0.05). After 12 weeks of resveratrol intervention, blood sugar, urea nitrogen and creatinine decreased, but the difference was not significant (P0.05). Compared with the normal control group, the ratio of urinary albumin to creatinine (albumin/creatinine ratio, ACR) in the diabetic group and the resveratrol group was significantly higher (P0.05); resveratrol treatment was compared with the diabetic group. ACR in the treatment group was significantly lower (P0.05). In the morphological aspect, the resveratrol treatment group had a significant reduction in the proliferation of mesangial cells and the increase of the extra membrane matrix in the diabetic group. In the molecular biology, the p-Akt/Akt of the Akt activity and the expression of NF- kappa B were significantly higher in the diabetic group and the resveratrol group than in the normal control group (P0.05). Compared with the diabetes group, the above indexes were significantly decreased in the resveratrol treatment group. Immunohistochemistry showed that the above proteins were expressed in the renal interstitium, renal tubules and glomeruli, and the change trend was consistent with the results of Western blot detection. The inflammatory factor PAI-1, the expression of -1 (intercellular AdhesionMolecule-1, ICAM-1) protein of intercellular adhesion molecule (intercellular AdhesionMolecule-1, ICAM-1) was expressed in sugar The urine sickness group and the resveratrol group were significantly higher than the normal control group (P0.05). Compared with the diabetic group, the above indexes were significantly decreased in the resveratrol group (P0.05). The immunohistochemical staining showed that the PAI-1 protein was expressed in the renal interstitium, renal tubules and glomeruli, and the change trend was consistent with the results of Western blot detection. Compared with the normal control group, the level of proliferating cell nuclear antigen (PCNA) mRNA increased significantly in the diabetic group (P0.05), and the level of PCNA mRNA in the resveratrol group was significantly lower than that in the diabetic group (P0.05). The immunohistochemical results showed that the PCNA positive cells in the kidney of the diabetic mice were significantly more than those of the normal control group (P0.05) per unit area of the diabetic group (P0.05). Resveratrol treatment significantly reduced the number of PCNA positive cells per unit area in the kidney of mice (P0.05).
To sum up, this study confirms that:
(1) resveratrol can significantly reduce the overexpression of cytokine NF- kappa B, PAI-1 and the level of cell proliferation under high glucose stimulation. It is said that veratrol can reduce the inflammatory reaction and cell proliferation of primary rat mesangial cells under high glucose environment.
(2) both resveratrol and Akt activity inhibitors can effectively reduce the abnormal increased Akt activity of rat mesangial cells under high glucose stimulation and reduce the overexpression of cytokines NF- kappa B and PAI-1. It is clear that veratrol is closely related to Akt/NF- kappa B pathway.
(3) after the successful establishment of the model of type 1 diabetic mice, the continuous use of resveratrol for 12 weeks, the ACR in the resveratrol treatment group decreased, the expression of PAI-1, ICAM-1 decreased, the pathological changes were reduced, and the number of PCNA positive cells in the renal tissue decreased. It was said that veratrol could significantly reduce the proteinuria, inflammation and mesangial cell proliferation caused by DN.
(4) the protective effect of resveratrol on diabetic nephropathy may be achieved by inhibiting the activity of Akt, reducing the expression of NF- kappa B protein, reducing the inflammatory response and inhibiting the proliferation of mesangial cells.
The main innovations of this study are as follows:
(1) for the first time in animal experiments, resveratrol can inhibit the proliferation of mesangial cells through the Akt/NF- kappa B pathway.
(2) the relationship between resveratrol and Akt activity inhibitors and the inflammatory mediators of DN, PAI-1, ICAM-1, was elucidated through two experiments in vivo and in vitro, and suggested that the above effects may be related to the Akt/NF- kappa B pathway.

【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R587.2;R692.9

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