本文選題：糖尿病腎病 + 免疫穩(wěn)態(tài)�。� 參考：《山東大學(xué)》2014年博士論文

【摘要】：背景： 糖尿病腎病是嚴(yán)重的糖尿病微血管并發(fā)癥,是導(dǎo)致終末期腎病的最常見原因,也是導(dǎo)致糖尿病患者死亡的主要原因。雖然傳統(tǒng)意義上認(rèn)為糖尿病腎病是一種非免疫系統(tǒng)疾病,但是越來越多的臨床和動(dòng)物實(shí)驗(yàn)研究發(fā)現(xiàn)糖尿病腎病中存在大量浸潤的免疫細(xì)胞、炎性介質(zhì)、細(xì)胞因子,細(xì)胞外基質(zhì),并與腎臟固有細(xì)胞損傷相互關(guān)聯(lián),這表明固有免疫系統(tǒng)的激活和炎癥機(jī)制在糖尿病腎病的發(fā)生發(fā)展中起重要作用。 固有免疫是機(jī)體抵抗外來致病因子入侵的第一道防線。主要通過模式識別受體(pattern recognition receptors,PRR)識別進(jìn)化上高度保守的病原相關(guān)分子模式(pathogen-associated molecular patterns,PAMP)或者損傷相關(guān)分子模式(damage-associated molecular patterns,DAMP),誘發(fā)組織處于持續(xù)炎性損傷狀態(tài)。目前模式識別受體中的細(xì)胞內(nèi)核苷酸結(jié)合寡聚化結(jié)構(gòu)域(nucleotide-binding oligomerization domain,NOD)蛋白家族,NOD樣受體(NOD-like receptors,NLR),是當(dāng)前研究的熱點(diǎn),其中對NOD2的研究較多。NOD2包含2個(gè)CARD結(jié)構(gòu)域,識別肽聚糖中的胞壁酰二肽(MDP),在炎癥穩(wěn)態(tài)中起重要作用。研究發(fā)現(xiàn)NOD2突變基因與克羅恩病和Blau綜合征的易感性有關(guān),這使NOD2在炎癥穩(wěn)態(tài)中的重要作用突顯了出來。NOD2不僅分布在炎癥細(xì)胞中,還廣泛存在于其他細(xì)胞,例如脂肪細(xì)胞和上皮細(xì)胞等。病理?xiàng)l件下,NOD2在激活這些細(xì)胞的炎癥反應(yīng)的過程中起重要作用。 胰島素抵抗(IR)貫穿二型糖尿病的整個(gè)發(fā)病過程,能夠?qū)е聶C(jī)體高血糖反應(yīng),長期高血糖引發(fā)的固有免疫和炎癥反應(yīng)能夠進(jìn)一步加重組織的胰島素抵抗?fàn)顟B(tài)。有研究表明胰島素抵抗與固有免疫系統(tǒng)的激活以及慢性低程度的炎癥反應(yīng)有關(guān)。足細(xì)胞作為腎小球?yàn)V過膜的主要組成部分,也是胰島素敏感細(xì)胞,且蛋白尿的生成與胰島素抵抗導(dǎo)致的足細(xì)胞損傷有關(guān)。足細(xì)胞可以依賴于細(xì)胞骨架微絲蛋白易化葡萄糖轉(zhuǎn)運(yùn)子GLUT1和GLUT4,同時(shí)依賴足細(xì)胞特異蛋白腎病蛋白(nephrin)可以促使富含GLUT1和GLUT4的微泡與細(xì)胞膜融合。因而,nephrin在足細(xì)胞胰島素敏感性上起著至關(guān)重要的作用。 研究發(fā)現(xiàn)NOD2在人和小鼠的腎小管上皮細(xì)胞表達(dá),Nod2敲除可以改善腎缺血再灌注引起的損傷,但有關(guān)NOD2在腎臟其他細(xì)胞中的表達(dá)分布以及是否在糖尿病腎病中發(fā)揮重要作用,迄今尚未見報(bào)道。 目的： 一、確定NOD2在糖尿病腎病活檢樣本和動(dòng)物模型中的表達(dá)情況,并明確NOD2是否與糖尿病腎病的炎癥病理過程有關(guān)。 二、從炎性反應(yīng)與足細(xì)胞的胰島素抵抗角度深入探討NOD2參與糖尿病腎病足細(xì)胞損傷中的作用及機(jī)制。 方法： 動(dòng)物學(xué)研究 實(shí)驗(yàn)采用選用8周野生型C57BL/6J小鼠和NOD2-/-小鼠各20只隨機(jī)分成四組,即野生型正常飲食組,野生型高脂飲食/STZ刺激組,NOD2-/-小鼠正常飲食組和NOD2-/-小鼠高脂飲食/STZ刺激組(normal-diet wild-type mice, HFD/STZ-induced wild-type mice,normal-diet NOD2-/-mice, HFD/STZ-induced NOD2-/-mice)。正常組給以正常飲食,高脂飲食/STZ刺激組給予持續(xù)高脂飲食14周和STZ刺激以制備糖尿病小鼠模型。通過采用PAS染色和電鏡分析兩種辦法,觀察各組腎小球病理改變變化。Western blot檢測NOD2在野生小鼠各器官中的表達(dá)以及野生糖尿病小鼠腎臟皮質(zhì)NOD2表達(dá)變化。連續(xù)切片免疫組化染色檢測糖尿病小鼠腎臟NOD2表達(dá)變化和浸潤的單核巨噬細(xì)胞表達(dá)NOD2的情況。進(jìn)行Elisa和實(shí)時(shí)定量RT-PCR方法檢測炎癥因子表達(dá)。通過組織免疫熒光染色和Western blot兩種方法檢測各組腎小球nephrin表達(dá)變化。相關(guān)疾病病人樣本研究 獲取正常人、糖尿病腎病病人、糖尿病非腎病病人、局灶性節(jié)段性腎小球硬化病人、IgA膜性腎病病人、膜性腎小球腎炎病人、紅斑狼瘡腎炎病人、腎微小病變病人活檢樣木。進(jìn)行免疫組化染色確定糖尿病腎病樣本NOD2表達(dá)變化和浸潤的巨噬細(xì)胞NOD2的表達(dá)情況。實(shí)時(shí)定量RT-PCR檢測NOD2mRNA含量,判斷NOD2mRNA與估算腎小球?yàn)V過率和24小時(shí)尿蛋白量的關(guān)系。體外實(shí)驗(yàn)研究 體外培養(yǎng)腎臟固有細(xì)胞,進(jìn)行RT-PCR檢測腎臟固有細(xì)胞NOD2mRNA的表達(dá)。體外模擬糖尿病腎病病理狀態(tài),Western blot檢測足細(xì)胞在高糖、糖基化終末產(chǎn)物(AGE)、腫瘤刺激因子-α(TNF-a)和轉(zhuǎn)化生長因子-β(TGF-p,糖尿病腎病常見損傷因子)刺激下NOD2的表達(dá)變化。MDP激活足細(xì)胞NOD2后,Western blot檢測phospho-ERK1/2、phospho-p38、phospho-JN、IκBα的變化評估MAPKs通路和NF-κB通路激活情況；實(shí)時(shí)定量RT-PCR檢測促炎因子的變化；流式細(xì)胞術(shù)測足細(xì)胞的凋亡；MDP刺激足細(xì)胞,葡萄糖攝取實(shí)驗(yàn)評估足細(xì)胞對葡萄糖的攝取情況：細(xì)胞免疫熒光觀察GLUT4在胞膜的分布變化；Western blot檢測GLUT4在細(xì)胞膜的表達(dá)變化；通過Western blot檢測MDP激活NOD2誘導(dǎo)胰島素受體底物-1絲氨酸殘基的磷酸化,免疫共沉淀法評估MDP影響胰島素誘導(dǎo)的胰島素受體底物-1酪氨酸殘基與p85亞基的結(jié)合從而判斷胰島素信號通路的變化情況。通過Western blot檢測高糖和MDP刺激對足細(xì)胞nephrin表達(dá)情況的影響；通過shRNA干擾技術(shù)檢測Nod2基因沉默對高糖條件下足細(xì)胞nephrin表達(dá)情況的影響。 結(jié)果： NOD2在腎臟細(xì)胞的表達(dá) 本課題首先檢測NOD2在腎臟組織和腎臟細(xì)胞中的表達(dá)。與成年小鼠小腸組織、脾臟、肺臟相比較,腎臟的表達(dá)量較高。這與以往研究NOD2器官特異性表達(dá)的結(jié)果相一致。NOD2在野生型和NOD2-/-小鼠腎臟和小腸石蠟切片的免疫組化染色進(jìn)一步顯示了NOD2的表達(dá)模式以及NOD2抗體免疫組化染色的特異性。小鼠腎小球系膜細(xì)胞、小鼠足細(xì)胞、人腎小球內(nèi)皮細(xì)胞以及人遠(yuǎn)端腎小管上皮細(xì)胞均表達(dá)NOD2。 人糖尿病腎病活檢樣本和HFD/STZ誘導(dǎo)的糖尿病小鼠的腎皮質(zhì)NOD2的表達(dá)升高 人糖尿病腎病活檢樣本石蠟切片的免疫組化染色發(fā)現(xiàn)NOD2表達(dá)上調(diào)。針對CD68和NOD2的連續(xù)切片染色可以在間質(zhì)和腎小球中觀察到CD68陽性的單核巨噬細(xì)胞浸潤,并且與NOD2共定位,這說明NOD2在腎臟固有細(xì)胞和浸潤的免疫細(xì)胞中表達(dá)增強(qiáng)共同導(dǎo)致了腎臟中NOD2的表達(dá)上調(diào)。實(shí)時(shí)定量RT-PCR分析進(jìn)一步證實(shí)糖尿病腎病活檢樣本NOD2mRNA水平升高。同時(shí),本課題也檢測了NOD2在其他類型的腎臟疾病中的表達(dá)。發(fā)現(xiàn)與正常對照相比,除腎微小病變病人(n=8)外,局灶性節(jié)段性腎小球硬化病人(n=7)、IgA膜性腎病病人(n=7)、膜性腎小球腎炎病人(n=6)和紅斑狼瘡腎炎病人(n=9)的腎活檢樣本的NOD2mRNA水平明顯升高。所有樣本中NOD2mRNA水平與估算腎小球?yàn)V過率成負(fù)相關(guān)(Spearman's r=-0.7274, P0.01)。在有蛋白尿的樣本中,NOD2mRNA水平與蛋白尿無明顯相關(guān)性(Spearman's r=-0.1384,P0.05)。 HFD/STZ誘導(dǎo)的糖尿病腎病小鼠模型中發(fā)現(xiàn),HFD/STZ誘導(dǎo)產(chǎn)生高血脂,增加血漿甘油三酯和游離脂肪酸含量,而血壓無明顯變化。Western blot和免疫組化分析發(fā)現(xiàn)HFD/STZ誘導(dǎo)的糖尿病腎病小鼠模型中腎NOD2的水平明顯升高,而且浸潤的炎癥細(xì)胞也同樣導(dǎo)致了腎臟NOD2的升高,這與糖尿病腎病病人的檢測結(jié)果是一致的。 NOD2缺失減輕糖尿病腎病小鼠腎臟損傷 與野生型糖尿病腎病小鼠相比,NOD2-/-的糖尿病腎病小鼠的蛋白尿明顯減少,同時(shí)伴隨系膜細(xì)胞增生和足細(xì)胞損傷減輕。進(jìn)一步實(shí)驗(yàn)表明,NOD2-/-糖尿病腎病小鼠雙腎和血清的促炎細(xì)胞因子和趨化因子水平減低,包括IL-1β、IL-6、 IL-8、TNF-α、單核細(xì)胞趨化蛋白-1(MCP-1)以及細(xì)胞內(nèi)粘附分子-1(ICAM-1)。糖尿病腎病小鼠腎臟組織中腎臟纖維化相關(guān)分子包括膠原IV和纖連蛋白的水平也降低。 高糖環(huán)境各因子刺激足細(xì)胞NOD2表達(dá)上調(diào) 足細(xì)胞NOD2表達(dá)上調(diào)具有葡萄糖濃度依賴性,其中甘露醇對照組NOD2的表達(dá)沒有明顯變化,說明可以排除滲透壓對NOD2的影響。進(jìn)一步檢測發(fā)現(xiàn)足細(xì)胞在糖基化終末產(chǎn)物、TNF-a和TGF-p的刺激下,NOD2的表達(dá)均顯著升高并呈濃度依賴性。MDP誘導(dǎo)MAPK信號通路激活、促炎遞質(zhì)的生成和足細(xì)胞凋亡 MDP刺激足細(xì)胞激活NOD2,檢測發(fā)現(xiàn)特異性細(xì)胞外液信號調(diào)節(jié)激酶(ERK)1/2.p38MAPK和c-Jun N-端激酶(JNK)磷酸化水平升高,且MDP以時(shí)間依賴的方式調(diào)控NF-κB信號通路的關(guān)鍵成分IκBα的降解。同時(shí),MDP增加足細(xì)胞促炎遞質(zhì)的生成,進(jìn)一步利用流式細(xì)胞術(shù)檢測發(fā)現(xiàn)MDP誘導(dǎo)足細(xì)胞凋亡。NOD2介導(dǎo)足細(xì)胞的葡萄糖吸收、GLUT4轉(zhuǎn)位和胰島素信號通路 在胰島素刺激下,足細(xì)胞葡萄糖攝取明顯增加,而MDP可以選擇性的減低胰島素誘導(dǎo)的2-脫氧葡萄糖的吸收。進(jìn)而免疫熒光染色和Western blot證明MDP破壞胰島素誘導(dǎo)的GLUT4轉(zhuǎn)位到細(xì)胞膜,這與NOD2激活減少胰島素誘導(dǎo)的足細(xì)胞葡萄糖吸收的實(shí)驗(yàn)結(jié)果相一致。進(jìn)一步檢測發(fā)現(xiàn)NOD2的激活引起IRS-1絲氨酸殘基的磷酸化,胰島素刺激后IRS-1酪氨酸殘基的磷酸化水平減輕。同時(shí)通過免疫共沉淀發(fā)現(xiàn),MDP降低胰島素刺激引起的p85亞基與磷酸化的IRS酪氨酸殘基之間的相互結(jié)合,影響下游P13K通路。高血糖時(shí)NOD2的激活降低nephrin的表達(dá) 免疫熒光分析和Western blot檢測發(fā)現(xiàn),在正常飲食小鼠nephrin染色沿著腎小球血管袢呈現(xiàn)流暢線型,但在糖尿病腎病小鼠nephrin明顯減少,在NOD2-/-糖尿病腎病小鼠又有所改善。在體外實(shí)驗(yàn)研究中,高糖降低足細(xì)胞nephrin的表達(dá),而MDP也降低足細(xì)胞nephrin的表達(dá)。更重要的是,本課題發(fā)現(xiàn)MDP引起足細(xì)胞actin微絲減少且胞漿actin呈顆粒狀分布說明MDP降低nephrin的表達(dá)與細(xì)胞骨架蛋白的改變相關(guān)。進(jìn)一步通過shRNA-NOD2轉(zhuǎn)染后發(fā)現(xiàn),Nod2沉默可以使高糖誘導(dǎo)的nephrin表達(dá)降低的程度減輕。 結(jié)論： 1.首次明確NOD2在人糖尿病腎病腎組織及糖尿病腎病小鼠模型中的表達(dá)上調(diào)。而NOD2-/-糖尿病小鼠的腎小球改變明顯減輕,蛋白尿情況得到改善,炎癥介質(zhì)的生成減少,提示NOD2在糖尿病腎病中可能發(fā)揮重要作用。 2.NOD2在腎臟疾病中均表達(dá)升高且NOD2水平與腎小球率過濾之間存在負(fù)相關(guān),與蛋白尿之間不存在明顯的相關(guān)關(guān)系,提示NOD2的表達(dá)上調(diào)很可能是人類炎癥相關(guān)腎臟疾病的共同特征。 3.糖尿病腎病病人和小鼠糖尿病動(dòng)物模型腎臟組織連續(xù)切片中NOD2與單核巨噬細(xì)胞標(biāo)記蛋白CD68共定位,表明NOD2在腎臟固有細(xì)胞和浸潤的免疫細(xì)胞中表達(dá)增強(qiáng)共同導(dǎo)致了腎臟中NOD2的表達(dá)上調(diào)。 4.足細(xì)胞中NOD2表達(dá)增高呈現(xiàn)葡萄糖濃度依賴性,同時(shí)伴隨促炎因子的增多和MAPKs及NF-κB信號通路的激活；NOD2激活后胰島素信號通路的水平降低,GLUT4轉(zhuǎn)位減少以及糖攝取量降低,提示NOD2通過調(diào)控炎癥機(jī)制參與足細(xì)胞的胰島素抵抗。 5.NOD2-/-糖尿病小鼠腎臟組織以及Nod2沉默的足細(xì)胞中高糖誘導(dǎo)的nephrin降低得到改善,提示NOD2通過影響nephrin的表達(dá)調(diào)控高糖誘導(dǎo)的足細(xì)胞功能失調(diào)。
[Abstract]:Background :

Diabetic nephropathy is a serious diabetic microvascular complication , which is the most common cause of end - stage renal disease and is the main cause of death in diabetic patients . Although it is traditionally considered that diabetic nephropathy is a non - immune system disease , more and more clinical and animal experimental studies have found that there are a large number of infiltrating immune cells , inflammatory mediators , cytokines , extracellular matrix in diabetic nephropathy , and correlated with the damage of the natural cells of the kidney . This suggests that the activation of the innate immune system and the mechanism of inflammation play an important role in the development of diabetic nephropathy .

In this paper , we find that NOD2 is associated with the susceptibility to Crohn ' s disease and Blau ' s syndrome . The NOD2 is not only distributed in inflammatory cells but also in other cells , such as fat cells and epithelial cells . NOD2 plays an important role in the activation of inflammatory responses of these cells .

Insulin resistance ( IR ) penetrates the whole pathogenesis of type 2 diabetes mellitus , can lead to hyperglycemia reaction , and the innate immunity and inflammatory response induced by long - term hyperglycemia can further aggravate the insulin resistance state of the tissues . The study shows that insulin resistance is related to the activation of the innate immune system and the chronic low degree of inflammatory response .

It was found that NOD2 was expressed in human and mouse renal tubular epithelial cells . Nod2 knock - out could improve renal ischemia - reperfusion injury , but the distribution of NOD2 in other cells of kidney and whether it plays an important role in diabetic nephropathy has not been reported to date .

Purpose :

1 . To determine the expression of NOD2 in diabetic nephropathy biopsy samples and animal models , and to determine whether NOD2 is related to the inflammatory pathological process of diabetic nephropathy .

Second , the role and mechanism of NOD2 in diabetic nephropathy induced by diabetic nephropathy were discussed in detail from the viewpoint of inflammatory response and insulin resistance of the foot cells .

Method :

Zoology Studies

Twenty - two randomly divided into four groups , i.e . wild - type normal diet group , wild type high - fat diet / insulin - stimulated group , NOD2 - / - mouse normal diet group and NOD2 - / - mouse high - fat diet - type mice ( normal - diet - induced wild - type mice , normal - diet NOD2 - / - mice , HFD - induced NOD2 - / - mice ) were randomly divided into four groups : wild - type normal diet group , wild - type high - fat diet - type mice , NOD2 - / - mouse normal diet group and NOD2 - / - mouse normal - diet wild - type mice . The expression of NOD2 in various organs of diabetic mice and the expression of NOD2 in kidney cortex of wild diabetic mice were observed by immunohistochemistry staining and Western blot .

The expression of NOD2 mRNA in diabetic nephropathy patients , diabetic nephropathy patients , diabetic nephropathy patients , focal segmental glomerulosclerosis patients , IgA membranous nephropathy patients , membranous glomerulonephritis patients , lupus nephritis patients and renal microlesions were determined .

The expression of NOD2 mRNA in kidney was detected by RT - PCR in vitro . Western blot was used to detect the expression of NOD2 in diabetic nephropathy . Western blot was used to detect the expression of NOD2 in high - sugar , glycosylated terminal products ( AGE ) , tumor - stimulating factor - 偽 ( TNF - a ) and transforming growth factor - 尾 ( TGF - p , diabetic nephropathy ) .
Real - time quantitative RT - PCR for the detection of pro - inflammatory factors ;
Flow cytometry was used to measure the apoptosis of foot cells .
The uptake of glucose was assessed by MDP stimulation of the foot cells and glucose uptake assay : the distribution of GLUT4 in the membrane was observed by immunofluorescence assay .
Western blot was used to detect the expression of GLUT4 in the cell membrane .
The expression of insulin receptor substrate - 1 tyrosine residue and p85 subunit was assessed by Western blot . The effect of high glucose and MDP stimulation on the expression of nephrin was detected by Western blot .
The effect of silencing of Nod2 gene on the expression of nephrin under high glucose condition was investigated by shRNA interference technique .

Results :

Expression of NOD2 in renal cells

In this study , the expression of NOD2 in renal tissue and kidney cells was first examined . The expression of NOD2 was higher than that of NOD2 in the small intestine tissues , spleen and lungs of adult mice . The expression pattern of NOD2 and the specificity of NOD2 antibody immunohistochemical staining were further demonstrated in both wild type and NOD2 - / - mouse kidney and small intestine paraffin sections . NOD2 was expressed in mouse glomerular mesangial cells , mouse foot cells , human glomerular endothelial cells , and human distal tubular epithelial cells .

Increased expression of NOD2 in renal cortex of diabetic mice induced by human diabetic nephropathy biopsy samples and HFD / induced diabetic mice

The expression of NOD2 mRNA in renal biopsy specimens of diabetic nephropathy patients ( n = 7 ) , IgA membranous nephropathy ( n = 7 ) , membranous glomerulonephritis ( n = 6 ) and lupus nephritis ( n = 9 ) were detected by RT - PCR . In the samples with proteinuria , the level of NOD2mRNA was not significantly correlated with that of proteinuria ( spearman ' s r = - 0.1384 , P0.05 ) .

The results of Western blot and immunohistochemistry showed that the levels of renal NOD2 in diabetic nephropathy mice were significantly higher than those of diabetic nephropathy .

NOD2 deletion reduces kidney damage in diabetic nephropathy mice

Compared with the wild - type diabetic nephropathy mice , the proteinuria of NOD2 - / - diabetic nephropathy mice was significantly decreased , accompanied by decreased proliferation of mesangial cells and injury of the foot cells . Further experiments showed that the levels of pro - inflammatory cytokines and chemokine levels in both kidney and serum of NOD2 - / - diabetic nephropathy mice were reduced , including IL - 1尾 , IL - 6 , IL - 8 , TNF - 偽 , monocyte chemoattractant protein - 1 ( MCP - 1 ) , and intracellular adhesion molecule - 1 ( ICAM - 1 ) . The levels of renal fibrosis - related molecules in kidney tissues of diabetic nephropathy mice , including collagen IV and fibronectin , were also reduced .

Up - regulation of NOD2 expression in human cells stimulated by high - sugar environment

There was no significant change in the expression of NOD2 in the expression of NOD2 , and the expression of NOD2 was significantly increased and the concentration - dependent manner was observed in the expression of NOD2 in the control group . The activation of MAPK signal pathway , the formation of pro - inflammatory and the apoptosis of the cells were induced by MDP .

MDP stimulates the activation of NOD2 , and the detection of extracellular fluid signal regulated kinase ( ERK ) 1 / 2.p38MAPK and c - Jun N - terminal kinase ( ERK ) 1 / 2 . p38MAPK and c - Jun N - terminal kinase have increased phosphorylation level , and MDP regulates the degradation of NF - 魏B signaling pathway in time - dependent manner .

It was found that the activation of NOD2 induced phosphorylation of IRS - 1 serine residue and decreased phosphorylation of IRS - 1 tyrosine residue after insulin stimulation .

Immunofluorescence analysis and Western blot analysis showed that nephrin staining in normal diet mice was streamlined along the glomerular vascular loop , but the nephrin expression in diabetic nephropathy mice was improved . In vitro experiments , high glucose decreased the expression of nephrin and MDP also decreased the expression of nephrin .

Conclusion :

1 . The expression of NOD2 was up - regulated in kidney tissues and diabetic nephropathy mice . NOD2 - / - diabetic mice had a marked decrease in glomerulus alteration , and proteinuria was improved , and the formation of inflammatory mediators decreased , suggesting that NOD2 might play an important role in diabetic nephropathy .

2 . There was a negative correlation between NOD2 level and glomerular filtration rate in renal disease . There was no obvious correlation between NOD2 and proteinuria , suggesting that the up - regulation of NOD2 was probably the common characteristic of human inflammation - related kidney disease .

3 . NOD2 co - located between NOD2 and single - core macrophage marker protein CD68 in diabetic nephropathy patients and diabetic animal models of diabetic rats , suggesting that the expression of NOD2 in kidney - specific cells and infiltrating immune cells together leads to an up - regulation of NOD2 in the kidney .

4 . The expression of NOD2 in foot cells showed glucose concentration - dependent , accompanied by increased pro - inflammatory factors and activation of MAPKs and NF - 魏B signaling pathways .
The level of insulin signaling pathway decreased , GLUT4 translocation decreased and glucose uptake decreased after NOD2 activation , suggesting that NOD2 was involved in the insulin resistance of the foot cells by regulating the inflammatory mechanism .

5 . The nephrin - induced decrease in nephrin induced by NOD2 - / - diabetic mice kidney tissues and Nod2 - silenced foot cells was improved , suggesting that NOD2 regulates the dysregulation of high glucose - induced foot cell dysfunction by influencing the expression of nephrin .
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R587.2;R692

【共引文獻(xiàn)】

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本文編號：2087061