本文選題：阿霉素 + 腎病�。� 參考：《山東大學》2016年博士論文

【摘要】：研究背景及研究目的：原發(fā)性腎病綜合征(Primary Nephrotic syndrome, PNS)是最常見的兒童腎臟疾病之一,其臨床癥狀是腎病范圍的蛋白尿、低白蛋白血癥、水腫和高膽固醇血癥。PNS的發(fā)病機制現(xiàn)仍未知,而且它是一種多元素性疾病。PNS按腎臟病理分為微小病變腎病綜合征(minimal change nephrotic syndrome,MCNS),局灶節(jié)段性腎小球硬化(focal segmental glomerulosclerosis,FSGS),系膜增生性腎小球腎炎(mesangial proliferative glomerulonephritis,MsPGN),和膜性增生性腎小球腎炎(membranoproliferative glomerulonephritis,MNGN)等。PNS主要病理類型是MCNS(77.1%)和FSGS(7.9%)�；純捍蠖紝に孛舾�,但少數(shù)患兒對激素依賴或抵抗,最后發(fā)展為終末期腎病。因此闡明PNS的發(fā)病機制,針對其發(fā)病過程進行藥物干預,可以為腎病患兒開辟新的診療途徑。白介素17(Interleukin-17,IL-17),是一種促炎的細胞因子,由活化的CD4+T細胞亞群(常稱為Th17)產(chǎn)生。IL-17家族由6種家庭成員構(gòu)成,它們分別是IL-17(又稱IL-17A), IL-17B, IL-17C, IL-17D, IL-17 E(又稱IL-25),和IL-17F。IL-17受體家族由5種成員組成,它們分別是IL-17RA、IL-17RB、 IL-17RC、IL-17RD和IL-17RE。近年來國內(nèi)外對IL-17在腎臟疾病方面的研究集中在狼瘡性腎炎、糖尿病腎病、腎小球腎炎、腎損傷和腎移植排斥損傷。有關(guān)IL-17在腎病綜合征的研究報道很少。我們知道T細胞參與PNS的發(fā)病機制,而Th17分泌的細胞因子是否參與PNS的免疫機制還不明確。有研究者提出,IL-17很可能是T細胞活化和炎癥之間的一座橋梁。Wang等發(fā)現(xiàn)Th17/IL-17通過下調(diào)podocalyxin表達水平,和誘導足細胞凋亡,從而促進PNS的發(fā)病。Liu等報道MCNS潛在的發(fā)病機制是Th17/Treg不平衡。新近少數(shù)研究資料表明IL-17在MCNS發(fā)病機制中起到主要的作用。新近資料顯示,利妥昔單抗可以通過抑制IL-17,影響B(tài)細胞的消耗,或者改變足細胞的細胞骨架,干預MCNS的發(fā)病機制。IL-17A產(chǎn)生的主要途徑是腎臟Th17細胞上的趨化因子受體CCR6與CCL20反應。IL-17信號是通過其與受體相結(jié)合來發(fā)揮作用。在炎癥反應時,IL-17A可以募集中性粒細胞和巨噬細胞,從而產(chǎn)生多肽類蛋白,細胞因子和趨化因子(CXCL1, CXCL2,和CXCL5)。CXCL1、CXCL2能夠促進中性粒細胞的趨化。IL-8也可以促進感染部位中性粒細胞的聚集,最后清除炎癥病灶。CXC趨化因子配體9(chemokine ligand9,CXCL9)和CXCL10能調(diào)節(jié)Thl。在胞內(nèi)病原體、腫瘤抗原以及干擾素-γ(interferon-γ,IFN-γ)和IL-12的誘導下,Th0向Thl分化；Thl分泌IFN-γ、IL-2等；Th2分泌IL-4。因此,我們可以認為IL-17相關(guān)的趨化因子是CCR6、CCL20,中性粒細胞相關(guān)的趨化因子是CXCL1、CXCL2、IL-8, Th1相關(guān)的趨化因子和細胞因子是CXCL9、CXCL10、IL-12、IFN-γ。目前,國內(nèi)外關(guān)于IL-17及相關(guān)趨化因子在PNS中的研究尚無報道。PNS的主要損傷是腎臟丟失蛋白質(zhì),PNS范圍的蛋白尿是由于腎小球濾過膜通透性的損害,和腎小管重吸收障礙所致。腎小球濾過屏障是由三層組成：內(nèi)皮細胞層,腎小球基底膜(glomerular basement membrane, GBM),和足細胞足突層。。腎小球疾病的特點大都是裂孔隔膜(slit diaphragm,SD)分子結(jié)構(gòu)的改變,和足突結(jié)構(gòu)重組(融合和消失)。足突消失和蛋白尿的最主要原因是GBM或足細胞一GBM之間相互作用的異常,SD區(qū)域損害,以及肌動蛋白細胞骨架和相關(guān)蛋白的改變。足細胞結(jié)構(gòu)的改變引發(fā)足細胞損傷,從而導致足突的丟失。足細胞缺乏是腎小球硬化的開始。絲裂原活化激酶(mitogen-activated protein kinase,MAPK)是細胞功能活動的應激通路,對于細胞的生長、發(fā)育、分裂、凋亡等起到重要作用。哺乳細胞的MAPK通路有四種：細胞內(nèi)信號調(diào)節(jié)酶(extracellular signal-regulated kinase,Erk)-1和-2,c-Jun N末端酶(c-Jun N-terminal kinase,JNK), p38MAPK和細胞內(nèi)單個調(diào)節(jié)酶-5(extracellular signal-regulated kinase,-5,Erk5/BMK1)。研究已證實,MAPK通路在急慢性炎癥中起到重要的作用。P38MAPK在抗腎小球基底膜腎炎中的表達增加,并且影響炎癥細胞的聚集和腎小管的損傷。本研究通過阿霉素(Adriamycin, ADR)誘導建立的小鼠腎病綜合征模型(微小病變型),觀察IL-17在腎臟組織和外周血水平的變化,以及IL-17相關(guān)趨化因子CCR6、CCL20,中性粒細胞相關(guān)趨化因子CXCL1、CXCL2、IL-8,Thl相關(guān)趨化因子CXCL9、CXCL10、IL-12、IFN-γ,三組因子在腎組織中的表達變化。同時對模型小鼠應用中和IL-17抗體進行干預,觀察其炎癥水平和腎臟功能情況的變化。從而探討IL-17在PNS中的促炎機制。此外,本研究亦通過體外培養(yǎng)小鼠腎足細胞,研究IL-17在腎足細胞炎癥中的分子作用機制,以及與MAPK信號路徑的相關(guān)性。進一步探討IL-17及其相關(guān)趨化因子在兒童PNS發(fā)病及發(fā)展中的作用,為臨床上進一步防治兒童PNS提供新的理論依據(jù)。研究方法：1.動物實驗：隨機將Balb/c小鼠分為三組,正常對照組,模型組(阿霉素腎病),IL-17中和抗體組,每組共10只小鼠。給予小鼠尾靜脈注射阿霉素誘導阿霉素腎病模型(微小病變型),1周后其中1組模型小鼠給予腹腔注射IL-17中和抗體,2周后將全部小鼠處死,留取尿液、血液和腎組織。24小時尿蛋白定量采取鄰苯三酚紅比色法測試,ELISA檢測血清IL-17、Cys C、 Kim-1、NGAL的濃度。應用HE染色、免疫組化DAB染色制作腎組織病理切片,觀察腎臟組織中IL-17的表達。IL-17相關(guān)趨化因子CCR6、CCL20的mRNA表達,中性粒細胞相關(guān)趨化因子CXCL1、CXCL2、IL-8 的 mRNA表達,Thl相關(guān)趨化因子CXCL9、CXCL10、IL-12、IFN-γ的mRNA表達,均使用熒光定量PCR進行檢測。2.腎足細胞培養(yǎng)：小鼠腎足細胞加入含10%胚胎小牛血清的1640倍的培養(yǎng)液,和10U/ml γ干擾素后,然后放入33℃孵育箱,細胞傳代培養(yǎng)；然后轉(zhuǎn)入無干擾素、37℃培養(yǎng)孵箱,使細胞分化2周后。足細胞種植于平皿,在無血清的清潔培養(yǎng)液中培養(yǎng)24小時,應用重組的小鼠IL-17蛋白100ng/ml,刺激小鼠腎足細胞共同孵養(yǎng)24小時。隨后應用Erk、p38抑制劑10umol/l分別與IL-17刺激的足細胞孵育24小時后；收集細胞,Western Blot檢測：小鼠腎足細胞中p38、Erk及p-p38、p-Erk的蛋白水平。在加用p38和Erk抑制劑后,中性粒細胞相關(guān)趨化因子IL-8、Th1相關(guān)趨化因子IL-12的mRNA表達,采取熒光定量PCR測定。結(jié)果：1.光鏡的觀察結(jié)果同對照組比較,模型組有球囊部分粘連,系膜細胞增生,基質(zhì)增多,腎小管腔部分出現(xiàn)蛋白管型,腎間質(zhì)炎癥細胞浸潤；中和IL-17抗體組比模型組輕。2.電鏡的觀察結(jié)果模型組與對照組比較,腎小球形態(tài)結(jié)構(gòu)輕微異常,足突普遍融合。IL-17中和抗體組病變較輕。3.各組小鼠腎組織IL-17蛋白表達DAB染色顯示,IL-17的陽性細胞多為胞質(zhì)染色陽性,正常腎組織中有少量IL-17的表達,主要集中在腎小管,而腎小球中無表達；模型組中,腎小管上IL-17表達顯著,它在腎小球中有少量表達；IL-17中和抗體組較模型組輕。同對照組比較,阿霉素腎病組、IL-17中和抗體組細胞的陽性著色度明顯增強,P0.05。模型組比IL-17中和抗體組細胞陽性著色度明顯增高,P0.05。4.各組小鼠腎組織IL-17相關(guān)趨化因子CCR6、CCL20的mRNA表達與正常對照組對比,模型組、IL-17中和抗體組CCR6、CCL20的mRNA表達均升高,P0.05。模型組的CCR6、CCL20mRNA表達比IL-17中和抗體組增強,P0.05。5.各組小鼠腎組織中性粒細胞相關(guān)趨化因子CXCL1、CXCL2、IL-8的mRNA表達與正常對照組比較,模型組、IL-17中和抗體組CXCL1、CXCL2、IL-8的mRNA表達均升高,P0.05。模型組比IL-17中和抗體組CXCL1、CXCL2、 IL-8的mRNA表達升高,P0.05。6.各組小鼠腎組織Thl相關(guān)趨化因子CXCL9、CXCL10、IL-12、IFN-γ的mRNA表達與正常對照組比較,模型組、IL-17中和抗體組CXCL9、CXCL10、IL-12、 IFN-γ的表達下降,P0.05。模型組比IL-17中和抗體組CXCL9、CXCL10、 IL-12、IFN-γ的表達降低,P0.05。7.各組小鼠血清IL-17水平的變化與正常對照組比較,模型組、IL-17中和抗體組的IL-17水平升高,P0.05。模型組比IL-17中和抗體組的IL-17水平升高,P0.05。8.各組小鼠腎功能指標血清KIM-1、NGAL、Csy C水平的變化與正常對照組比較,模型組、IL-17中和抗體組的KIM-1、NGAL、Csy C血清水平均升高,P0.05。模型組比IL-17中和抗體組的KIM-1、NGAL、 Csy C水平升高,P0.05。9.小鼠腎足細胞中p38、Erk及p-p38、p-Erk的蛋白水平與正常組比較,IL-17刺激組Ep-Erk、p38、p-p38的蛋白表達水平升高,其中p-p38的蛋白水平升高最明顯。10.應用p38抑制劑和Erk抑制劑后,中性粒細胞相關(guān)趨化因子IL-8 mRNA表達與正常組對比,IL-17刺激組、p38抑制劑組、Erk抑制劑組的IL-8 mRNA表達均明顯升高,P0.05。與IL-17刺激組比較,p38抑制劑組、Erk抑制劑組IL-8mRNA表達均下降,P0.05。p38抑制劑組比Erk抑制劑組的IL-8 mRNA表達明顯升高,P0.05。11.應用p38抑制劑和Erk抑制劑后,Thl相關(guān)趨化因子IL-12 mRNA表達與正常組對比,IL-17刺激組IL-12 mRNA表達明顯下降,p38抑制劑組、Erk抑制劑組均明顯升高,P0.05。與IL-17刺激組比較,p38抑制劑組、Erk抑制劑組IL-12 mRNA表達均明顯升高,P0.05。p38抑制劑組比Erk抑制劑組IL-12 mRNA明顯升高,P0.05。結(jié)論：1.在阿霉素誘導的小鼠腎病模型中,腎組織IL-17表達異常增加,可以使中性粒細胞募集,參與ADR小鼠的炎癥病理過程,少量的IL-17對正常腎臟功能的維持有一定作用。2.在阿霉素誘導的小鼠腎病模型中,血清IL-17的水平明顯增高,提示IL-17促進ADR小鼠的炎癥過程,而且它還能促使Thl細胞分化降低,大量的IL-17可以導致ADR小鼠嚴重的腎功能損害。3.小鼠腹腔注射中和IL-17抗體能夠降低ADR小鼠血清IL-17的水平,減輕中性粒細胞募集,中和IL-17抗體抑制Thl細胞分化降低,腎功能獲得改善。4.IL-17可能通過MAPK信號通路對小鼠腎足細胞炎癥因子進行調(diào)控。5.IL-17能夠激活p38及Erk路徑信號,此過程中p38路徑信號是主要的。6.IL-17促進中性粒細胞聚集,產(chǎn)生炎癥反應,并且改變了天然CD4+T細胞向Th1/Th2分化的平衡,誘導其向Th2分化,抑制其向Thl分化。
[Abstract]:Research background and purpose: Primary Nephrotic syndrome (PNS) is one of the most common renal diseases in children. The clinical symptoms are proteinuria, hypoalbuminemia, edema, and hypercholesterolemia, the pathogenesis of.PNS in nephrotic range is still unknown, and it is a multielement disease.PNS by the kidney. The pathology was divided into minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (focal segmental glomerulosclerosis, FSGS), mesangial proliferative glomerulonephritis (mesangial proliferative glomerulonephritis,), and membranous proliferative glomerulonephritis. Ephritis, MNGN) and other major pathological types of.PNS are MCNS (77.1%) and FSGS (7.9%). Most of the children are sensitive to hormone, but a few children are dependent on or resisted by hormone, and finally develop to end-stage renal disease. Therefore, the pathogenesis of PNS and the drug intervention in the pathogenesis of the disease can open up a new way of diagnosis and treatment for children with kidney disease. IL 17 (Inte). Rleukin-17, IL-17) is a pro-inflammatory cytokine, produced by the activated CD4+T cell subgroup (often called Th17). The.IL-17 family is composed of 6 family members. They are IL-17 (also known as IL-17A), IL-17B, IL-17C, IL-17D, IL-17 E (also known as Th17). -17RC, IL-17RD, and IL-17RE. have focused on the study of IL-17 for renal disease in recent years in lupus nephritis, diabetic nephropathy, glomerulonephritis, renal injury and renal transplantation rejection. There are few reports about IL-17 in nephrotic syndrome. We know that T cells are involved in the pathogenesis of PNS, and Th17 secreted cytokines are The immune mechanism involved in PNS is not clear. Some researchers suggest that IL-17 is likely to be a bridge between T cell activation and inflammation, such as a bridge.Wang, and so on, that the pathogenesis of MCNS latent by Th17/IL-17 by downregulating the podocalyxin expression level, and inducing the apoptosis of the podocyte, and thus promoting the pathogenesis of PNS, is Th17/Treg imbalances. Several research data show that IL-17 plays a major role in the pathogenesis of MCNS. Recent data show that rituximab can inhibit IL-17, affect the consumption of B cells, or change the cytoskeleton of the podocytes. The main way to interfere with the pathogenesis of MCNS,.IL-17A, is the chemokine receptor CCR6 and CCL20 on the renal Th17 cells. The.IL-17 signal is combined with the receptor. In the inflammatory response, IL-17A can raise the concentration of granulocytes and macrophages to produce polypeptide proteins, cytokines and chemokines (CXCL1, CXCL2, and CXCL5).CXCL1, CXCL2 can promote the chemotaxis.IL-8 of neutrophils and can promote neutrophil in the infected site. .CXC chemokine ligand 9 (chemokine ligand9, CXCL9) and CXCL10 can regulate Thl. in the intracellular pathogen, tumor antigen and interferon - gamma (interferon- gamma, IFN- gamma) and IL-12, and Th0 toward Thl; Thl secretes gamma, and so on. CCR6, CCL20, neutrophil related chemokines are CXCL1, CXCL2, IL-8, and Th1 related chemokines and cytokines are CXCL9, CXCL10, IL-12, IFN- gamma. Currently, there is no report on IL-17 and related chemokine in PNS. The damage of glomerular filtration membrane permeability and renal tubular reabsorption disorders. The glomerular filtration barrier consists of three layers: the endothelial cell layer, the glomerular basement membrane (glomerular basement membrane, GBM), and the podocyte Poddar layer.. the characteristics of the glomerular diseases are the changes in the molecular structure of the slit diaphragm (SD), and the changes in the molecular structure of the slit diaphragm. The most important reason for the disappearance of podocyte structure (fusion and disappearance). The most important reason for the disappearance of podocyte and proteinuria is the abnormality of the interaction between GBM or GBM, the damage of the SD region, and the changes of the actin cytoskeleton and related proteins. The changes of the podocyte structure cause the foot cell damage and the loss of the poddate. The deficiency of the podocyte is a small kidney. The beginning of the hardening of the ball. Mitogen-activated protein kinase (MAPK) is the stress pathway of cell function activity. It plays an important role in cell growth, development, division and apoptosis. There are four kinds of MAPK pathway in mammalian cells: intracellular signal regulating enzyme (extracellular signal-regulated kinase, Erk) -1 and -2, c-Jun C-Jun N-terminal kinase (JNK), p38MAPK and intracellular single regulatory enzyme -5 (extracellular signal-regulated kinase, -5, Erk5/BMK1). Studies have shown that the MAPK pathway plays an important role in acute and chronic inflammation and increases the expression in anti glomerular basilar glomerulonephritis and affects the aggregation of inflammatory cells and renal tubules. In this study, the mouse nephrotic syndrome model (small lesion type) induced by Adriamycin (ADR) was used to observe the changes in the level of IL-17 in the renal tissue and peripheral blood, as well as the IL-17 related chemokine CCR6, CCL20, and neutrophil related chemokine related chemokine, CXCL1, CXCL2, IL-8, Thl related chemokine CXCL9, CXCL10, Thl. Gamma, three groups of factors in the renal tissue expression changes. Meanwhile, the model mice were used to neutralize the IL-17 antibody and observe the changes in the inflammatory level and renal function. Thus the proinflammatory mechanism of IL-17 in PNS was explored. In addition, this study also studied the molecules of renal foot cells in vitro by culture in mice, and studied the molecules of IL-17 in the inflammation of the renal poddine. The mechanism of action and the correlation with the MAPK signal pathway. Further explore the role of IL-17 and its related chemokines in the pathogenesis and development of children's PNS, and provide a new theoretical basis for the further prevention and treatment of children's PNS. 1. animal experiments: randomly divided Balb/c mice into three groups, normal control group, model group (adriamycin) Nephrosis), IL-17 neutralization antibody group, 10 mice in each group. Adriamycin induced adriamycin induced nephropathy model was induced by adriamycin in the tail vein of mice. After 1 weeks, 1 models of mice were injected with IL-17 neutralization antibody. After 2 weeks, all mice were killed and urine was left, and.24 hour urine protein in blood and kidney tissues was quantified by o-phenolol. The concentration of IL-17, Cys C, Kim-1, NGAL in serum was measured by ELISA. HE staining, immunohistochemical DAB staining was used to make pathological sections of renal tissue, and the expression of.IL-17 related chemokine in renal tissue was observed. The mRNA expression of CXCL9, CXCL10, IL-12, IFN- gamma,.2. renal podocyte culture was detected by fluorescence quantitative PCR: mice kidney foot cells added 1640 times the culture solution containing 10% embryo calf serum, and 10U/ml gamma interferon, and then incubated at 33 centigrade and cultured for generation, then transferred to no interferon and incubated at 37 centigrade to make cells After 2 weeks of differentiation, the Poddar was cultivated in a Petri dish and cultured for 24 hours in a serum-free cleaning medium. The recombinant mouse IL-17 protein 100ng/ml was used to stimulate the mouse kidney foot cells to incubate for 24 hours. Then, Erk, p38 inhibitor 10umol/l was incubated with IL-17 stimulated podar respectively for 24 hours, and cells were collected and Western Blot detected: small The protein level of p38, Erk and p-p38, p-Erk in rat renal podropoda. After adding p38 and Erk inhibitors, the expression of neutrophil related chemokine IL-8, Th1 related chemokine IL-12 mRNA expression and fluorescence quantitative PCR determination. Results: the results of the 1. light microscopy were compared with the control group, the model group had partial adhesion of balloon, mesangial cell proliferation and matrix. In addition, the renal tubular cavity partially appeared protein tube type and renal interstitial inflammatory cell infiltration, and the observation result model group of neutralizing IL-17 antibody group compared with the model group was compared with the control group, the glomerular morphology and structure were slightly abnormal, and the podocyte process was generally fused with the.IL-17 neutralization antibody group and the IL-17 protein expression of the renal tissue of the kidney tissues of the mice with light.3. was stained with DAB. The positive cells of IL-17 were mostly cytoplasmic staining positive, and a small amount of IL-17 expression in normal renal tissue, mainly concentrated in the renal tubules, but no expression in the glomeruli; in the model group, the expression of IL-17 on the renal tubules was significant, and it had a small amount of expression in the glomeruli; the IL-17 neutralization antibody group was lighter than the model group. Compared with the control group, the adriamycin nephrotic group, IL- The positive coloring degree of cells in the 17 neutralization antibody group was obviously enhanced and the positive coloring degree of the P0.05. model group was significantly higher than that of the IL-17 neutralization antibody group. The IL-17 related chemokines in the renal tissue of P0.05.4. mice were CCR6, the mRNA expression of CCL20 was compared with the normal control group. The CCR6 in the model group, the IL-17 and the antibody groups increased, the mRNA expression of CCL20 was increased, P0.05. modules were increased. The expression of CCR6 and CCL20mRNA in the group was stronger than that of the IL-17 neutralization antibody group. The expression of mRNA expression of neutrophils related chemokine in the renal tissue of each group of P0.05.5. was compared with that of the normal control group. The expression of CXCL1, CXCL2, and IL-8 was higher in the model group and in the IL-17 neutralization antibody group. The expression of mRNA increased, and the expression of mRNA expression of Thl related chemokines, CXCL10, IL-12, IFN- gamma in the kidney tissues of P0.05.6. mice was compared with the normal control group. The expression of CXCL9, CXCL10, IL-12, and gamma decreased in the model group and in the IL-17 neutralization antibody group, and the expression of the model group was lower than that of the neutralization antibody group. The level of serum IL-17 in mice was compared with that in the normal control group. The level of IL-17 in the model group and the IL-17 neutralization antibody group increased and the IL-17 level of the P0.05. model group was higher than that of the IL-17 neutralization antibody group. The changes of the serum KIM-1, NGAL, Csy C in the P0.05.8. groups were compared with those of the normal control group, the model group, the IL-17 neutralization antibody group and the normal control group. The level of serum M-1, NGAL, and Csy C increased, and the level of KIM-1, NGAL, Csy C in the P0.05. model group was higher than that of the IL-17 neutralizing antibody group. The expression of neutrophil related chemokine IL-8 mRNA was compared with that of normal group after p38 inhibitor and Erk inhibitor. The IL-8 mRNA expression in IL-17 stimulation group, p38 inhibitor group and Erk inhibitor group increased obviously. P0.05. and IL-17 stimulation group were compared with p38 inhibitor group and inhibitor group. The expression of IL-8 mRNA in the agent group was significantly higher. The expression of Thl related chemokine IL-12 mRNA expression was compared with the normal group after P0.05.11. application of p38 inhibitor and Erk inhibitor. The IL-12 mRNA expression in the IL-17 stimulation group decreased obviously, and the p38 inhibitor group and the inhibitor group all increased obviously. The expression of A was significantly increased, and the P0.05.p38 inhibitor group was significantly higher than that of the Erk inhibitor group IL-12 mRNA. P0.05. conclusion: 1. in the adriamycin induced mouse nephropathy model, the expression of IL-17 in the renal tissue is abnormal, which can raise the neutrophils and participate in the pathological process of inflammation in ADR mice. A small amount of IL-17 can maintain the normal function of the kidney. In the mouse nephropathy model induced by adriamycin, the level of serum IL-17 increased significantly, suggesting that IL-17 promotes the inflammatory process in ADR mice, and it can also promote the decrease of the differentiation of Thl cells. A large number of IL-17 can cause serious impairment of renal function in ADR mice, and the peritoneal injection of.3. mice and IL-17 antibody can reduce the IL-17 of ADR mice in.3. mice. Level, alleviating neutrophils recruitment, neutralizing IL-17 antibody and inhibiting Thl cell differentiation, and renal function improvement,.4.IL-17 may regulate the inflammatory factors of renal podocyte in mice by MAPK signaling pathway and.5.IL-17 can activate p38 and Erk pathway signals. In this process, p38 path signal is the main.6.IL-17 promoting neutrophil aggregation. It produces inflammatory response and changes the balance of natural CD4+T cell differentiation to Th1/Th2, induces differentiation into Th2 and inhibits Thl.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R726.9

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