炎症加重脂质诱导的肾脏损伤及阿托伐他汀干预作用的实验研究
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摘要
第一部分:炎症加重脂质诱导的肾脏损伤
目的:探讨炎症是否加重脂质诱导的肾脏的损伤。
方法:采用雄性C57BL/6小鼠,将小鼠随机分为三组:普通饮食组(A1)、高脂饮食组(B1)、高脂+炎症组(由皮下注射0.5ml 10%酪蛋白(Casein)/隔天诱导)(C1)。14周后处死,检测血清中IL-6、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)的水平。油红“O”染色及酶法检测肾组织内脂质沉积情况。HE、PAS、Masson染色观察肾脏形态学改变。(Real-time PCR,RT-PCR)实时荧光定量PCR和免疫组化技术(IHC)分别检测肾组织转化生长因子(TGF-β1)、纤维连接蛋白(FN)、I型胶原(Collagen I)、IV型胶原(Collagen IV)的基因与蛋白表达。
结果:与B1组比较,C1组血清中的IL-6显著升高(P<0.05),表明皮下注射Casein成功建立了系统慢性炎症小鼠模型。与A1组相比,B1组TC、LDL-C显著升高(P<0.01)。与B1组比较,C1组的血清的TC、LDL-C水平显著下降(P<0.05),而肾脏组织总胆固醇、胆固醇酯水平显著升高(P<0.05),病理学检测发现系膜细胞的增生和系膜基质的扩张,GSI显著增高(P<0.05)。RT-PCR及免疫组化检测发现炎症上调了TGF-β1、Collagen I、Collagen IV的表达(P<0.05)。
结论:炎症状态下,血浆胆固醇水平并不与肾脏损害呈正相关。炎症促进血清里的胆固醇不断进入肾脏组织细胞,降低了血清中的脂质水平,加重了脂质诱导的肾脏损伤。
第二部分:SREBP-LDLr/HMGCoA还原酶途径在炎症加重脂质诱导肾脏损伤的作用
目的:探讨胆固醇调节元件结合蛋白裂解蛋白(SCAP)-胆固醇调节元件结合蛋白2(SREBP2)-低密度脂蛋白受体(LDLr)/羟甲基戊二酸单酰CoA还原酶(HMGCoA还原酶)途径在炎症加重脂质诱导的肾脏损伤中的作用。
方法:在第一部分研究的动物模型上,RT-PCR检测SCAP,SREBP2、HMGCoA还原酶和LDLr基因水平,Western blot(WB)检测相应蛋白表达量。有相关趋势的变量采用Pearson相关分析。
结果:与B2组相比,C2组SCAP,SREBP2、HMGCoA还原酶和LDLr基因与蛋白表达显著上调(P<0.05),并且HMGCoA还原酶和LDLr蛋白的表达与肾脏组织沉积的胆固醇酯(CE)成正相关(P<0.05)。
结论:炎症可以通过上调SCAP-SREBP2-LDLr/HMGCoA还原酶的表达,促进胆固醇的合成和摄取,加重了脂质在肾脏的沉积,加重诱导了肾脏的损伤。
第三部分:炎症加重SR-A/CD36/ApoE三敲小鼠脂质诱导的肾脏损伤及主要机制
目的:应用SR-A/CD36/ApoE三敲除小鼠模型,旨在探讨清道夫受体CD36、SR-A及LDLr在炎症加重脂质介导的肾脏损伤的作用。
方法:C57BL/6来源的雄性SR-A/CD36/ApoE三敲除小鼠,将小鼠随机分为三组:普通饮食组(A2)、高脂饮食组(B2)、高脂+炎症组(C2)。14周后处死,检测血清中淀粉样蛋白(SAA)、IL-6、肌酐(Scr)、尿素氮(BUN)、TC、TG、LDL-C、和HDL-C水平。检测尿蛋白/尿肌酐的水平。油红“O”染色及酶法检测肾组织内脂质沉积情况。HE,PAS,Masson方法观察肾脏形态学改变。RT-PCR技术检测肾组织TGF-β1、FN、Collagen I、Collagen IV、a肌动蛋白(a-SMA)、LDLr、SREBP2、SCAPmRNA表达。IHC与WB技术检测TGF-β1、FN、Collagen I、Collagen IV、a-SMA、LDLr、SREBP2-N、SCAP蛋白表达。
结果:C2组血清炎症因子SAA,IL-6显著高于B2及A2组,表明炎症模型成功建立(P<0.05)。C2组血清中TC、LDL-C、HDL-C显著低于B2组(P<0.05),肾脏胆固醇,胆固醇酯的沉积却显著升高(P<0.05),血清Scr,BUN,尿蛋白/尿肌酐显著升高(P<0.05)。肾脏病理学检查发现C2组肾小球基底膜增厚,肾小管上皮细胞变性萎缩,蛋白管型及炎症细胞浸润等改变,GSI、TII显著高于B2组(P<0.05)。进一步检测发现炎症上调了肾脏Collagen I、Collagen IV、a-SMA、TGF-β1、FN mRNA与蛋白的表达(P<0.05)。炎症还显著促进了LDLr、SCAP、SREBP2mRNA及蛋白质的表达(P<0.05)。
结论:炎症可以通过SREBP2-SCAP-LDLr途径而非CD36/SR-A途径促进了脂质从血清向肾脏的积聚,加重了脂质诱导的肾脏损害。
第四部分:阿托伐他汀非依赖降血脂的肾脏的保护作用
目的:探讨阿托伐他汀的肾脏保护作用及潜在机制。
方法:在第三部分实验的同时,采用SR-A/CD36/ApoE三敲除小鼠设立高脂饮食+2mg/kg/d阿托伐他汀(D1)组,以A1、A2组为对照,B2组为模型组。检测血清IL-6、SAA的水平及脂质水平。油红“O”染色及酶法检测肾组织内脂质沉积情况。HE,PAS,Masson染色观察肾脏形态学改变。RT-PCR与IHC分别检测肾组织TGF-β1、FN、Collagen I、Collagen IV、a-SMA的基因与蛋白表达。
结果:与B2组比较,D1组显著减少了肾脏组织胆固醇、胆固醇酯沉积(P<0.05),显著改善了蛋白尿与肾功能(P<0.05),但是血清中的TC、LDL-C水平无显著的降低(P>0.05)。与B2组比较,D1组可以显著减少高脂饮食诱导的肾脏组织系膜细胞的增生,系膜基质的沉积等病理改变,GSI显著降低(P<0.05)。进一步检测发现D1组显著降低了肾脏组织TGF-β1的基因与蛋白表达(P<0.05),进而显著降低FN、Collagen I、Collagen IV、a-SMA的基因与蛋白表达(P<0.05)。
结论:阿托伐他汀可以不依赖于降血脂,而是通过降低肾脏组织TGF-β1,独立于SRA、CD36受体途径而发挥肾脏保护作用。
第五部分:炎症应激导致他汀抵抗作用
目的:本课题组体外实验已经证明炎症可以导致肝脏细胞对他汀药物的抵抗,本部分将从体内实验进一步探讨炎症反应是否影响阿托伐他汀的肾脏保护作用。
方法:在第三部分实验的同时,对高脂+炎症模型的小鼠加用阿托伐他汀2mg/kg/d(D2)和10mg/kg/d(D3)干预实验,以A2、D1、B2、C2组为对照,酶法检测血清的TC、LDL-C、TG、HDL-C水平与SAA、IL-6水平。HE、PAS、Masson染色方法观察肾脏形态学改变,酶法及油红“O”染色检测肾脏组织中胆固醇的沉积。RT-PCR检测肾组织TGF-β1、FN、Collagen I、Collagen IV、a-SMA的基因表达。
结果:与C2组对比,D2、D3组不能有效降低血脂水平(P>0.05)。与B2比较,D3组可以显著降低血脂水平(P<0.05)。与C2组对比,D2组不能显著的降低肾脏组织胆固醇的沉积、血清肌酐水平(P>0.05)及改善肾脏病理结构的损伤,D3组可显著降低肾脏组织胆固醇的沉积及改善肾脏的病理(P<0.05)。并且,D2组不能显著降低Collagen I、Collagen IV基因的表达(P>0.05),而D3组能显著降低FN、Collagen I、Collagen IV、a-SMA所有基因的表达(P<0.05)。
结论:炎症影响阿托伐他汀肾脏保护作用的疗效,在炎症环境中要达到相同效果需要增大剂量。而导致这个现象的潜在机制值得进一步探讨。
第六部分:重庆汉族儿童单核细胞趋化蛋白-1基因多态性及表达水平与结核病易感性的关系
目的:探讨MCP-1基因启动子区2518A/G多态性、血清MCP-1蛋白表达水平与结核病的相关关系。
方法:研究对象为100例儿童结核病、100例成人结核病以及相应的200例健康对照。序列特异性引物PCR(PCR-SSP)技术检测MCP-1基因启动子区2518A/G多态性。ELISA方法测定相应不同基因型患者和对照血清MCP-1水平。
结果:(1)总体结核病组2518GG基因型频率为65%,明显高于相应的健康对照组(27%)(P<0.05);(2)MCP-1基因启动子区2518位点GG基因型患结核病机率高于AA基因型,且儿童GG基因型发病的危险性高于成人GG基因型(P<0.05);(3)2518 GG基因型的MCP-1水平高于AA基因型和AG基因型。结核组高于正常组,儿童组高于成人组(P<0.05)。
结论:在中国重庆地区汉族人中,MCP-1-2518位GG基因型作为结核病可能的危险因素,在儿童结核病的发病中占有更重要的地位。
PART 1: INFLAMMATORY STRESS EXACERBATES LIPID MEDIATED RENAL INJURY
Objective:The aim of this part was to observe the influence of in-flammation on lipid metabolism disturbance and the progression of renal injury.
Methods:C57BL/6 mice were randomized into normal diet (A1), high fat diet (B1) and high fat diet plus casein injection (C1) (induce inflamma-tion) groups. Animals were sacrificed after 14 weeks, terminal blood sam-ples were taken for cholesterol (TC), triglycerides (TG), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and interleukin-6 (IL-6) assays. Red O stain and intracellular cholesterol concentration assay were performed. The morphological changes of kidney were examied by HE, PAS, Masson staining. The mRNA levels and protein expression of transforming growth factor-β(TGF-β1), collagen type I (Collagen I) and type IV (Collagen IV), Fibronectin (FN) were determined by Real-Time Polymerase Chain Reac-tion (RT-PCR) and immunohistochemistry (IHC) assessments.
Results: Blood IL-6 levels were higher, while TC and LDL-C were lower in the C1 group compared to B1 group (P<0.05). Lipid accumulation in the kidney was more extensive in C1 group despite lower blood lipid levels by ORO staining and quantitative analysis (P<0.05). PAS, Masson and HE staining demonstrated casein injection induced structural changes characterized by mesangial expansion in the kidney. The GSI was signifi-cantly higher in C2 group than those of other group (P<0.05). These ab-normalities were associated with increased gene and protein expression of Collagen I, Collagen IV, and TGF-β1.
Conclusions: Low blood cholesterol levels may be associated with high risk for chronic renal injury under inflammatory stress. Inflammation exacerbates lipid accumulation in kidney by diverting lipid from plasma to kidney.
PART 2: THE ROLE OF SREBP2/LDLR/ HMG-COA REDUC-TASE PATHWAY IN INFLAMMATORY STRESS EXACER-BATES LIPID MEDIATED RENAL INJURY
Objective: To explore the role of the sterol regulatory element binding protein cleavage protein (SCAP)-sterol regulatory element binding protein 2 (SREBP2)-low density lipoprotein receptor (LDLr) / 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) pathways in the process of inflammation stress exacerbating lipid mediated renal injury.
Methods: On the basis of part I, the genes of LDLr, SREBP2, SCAP, HMGCoA reductase involved in cholesterol negative feedback pathways were determined by RT-PCR and western-blotting (WB) as well. Some variables were analysis by Pearson correlation assesment.
Results: The mRNA of SCAP, SREBP2, LDLr, and HMGCoA reduc-tase as well as protein levels were markedly enhanced in C1 group com-pared with B1 group (P<0.05). Casein injection increased LDLr, HMGCoA reductase gene and protein expression in the kidney, probably by disrupting the intracellular cholesterol sensor, regulatory function of SREBP cleavage activating protein (SCAP). Futher, the protein level of HMGCoA reductase and LDLr was positively related to CE deposition in kidney (P<0.05).
Conclusion: Inflammation possibly exacerbates lipid induced-renal injury through the SCAP-SREBP2-LDLr/HMGCoA reductase pathways by abnormal cholesterol synthesising and uptaking.
PART 3: INFLAMMATORY STRESS EXACERBATES LIPID MEDIATED RENAL INJURY IN SR-A/CD36/APOE TRIPLE KNOCK-OUT TRIPLE-KNOCKOUT MICE
Objectives: This study was designed to investigate whether inflam-matory stress exacerbates lipid accumulation in lipid-mediated glomerular injury and, thereby exacerbating the progression of renal injury by non–scavenger receptor–mediated pathways in vivo.
Methods: Male SR-A/CD36/ApoE triple Knock-out (KO) mice were randomly divided into normal diet (A2), high fat diet (B2) and high fat diet plus inflammation groups (C2). Animals were sacrificed after 14 weeks, terminal blood samples were taken for creatinine (Scr), urea nitrogen (BUN), TC, TG, and LDL-C, HDL-C, amyloid A (SAA) and IL-6 assays. Renal sections were used for histological and IHC assessments. Renal histopa-thology was quantified using a glomerulosclerosis index (GSI) and a tubu-lointerstitial injury index (TII). The lipid accumulation in kidney was evaluated by Oil Red O staining and quantitative analysis. The mRNA and protein expression of TGF-β1, Collagen I, Collagen IV, FN, a-smooth mus-cle actin (a-SMA), SREBP2, SCAP, LDLr were analyzed by RT-PCR and WB analysis.
Results: Blood levels of SAA and IL-6 were higher (P<0.05), while TC, LDL-C and HDL-C were lower in the C2 group compared to B2 group (P<0.05). Meanwhile, lipid accumulation in the kidney was more extensive in C2 group despite lower blood lipid levels (P<0.05). Casein injection ex-acerbated renal function failure and proteinuria compared to B2 group (P<0.05). Casein injection induced massive structural changes. The GSI and TII were significantly higher in C2 group than those of B2 group. These abnormalities were associated with increased gene and protein expression of Collagen I, Collagen IV, TGF-β1, a-SMA, and FN. Further analysis showed that casein injection increased LDLr, SREBP2, and SCAP gene and protein expression in the kidney.
Conclusions: Non scavenger receptor-mediated alternative atherogenic pathways are operational, and SCAP-SREBP2-LDLr pathway may be the dominant mechanism for inflammatory stress exacerbating lipid mediated renal Injury.
PART 4: ENO-PROTECTIVE EFFECTS OF ATORVASTATIN INDEPENDENT OF CHOLESTEROL LOWERING
Objective: This part was to investigate whether Atorvastatin de-creased renal lipid accumulation and renal injury independent of the lipid-lowering effect.
Methods: Male SR-A/CD36/ApoE triple KO mice were randomly as- signed to receive high fat diet plus Atorvastatinn treatment group (D1) (2mg/kg/d), other groups of A1, A2 as control groups and B2 as model group. Terminal blood samples were taken for cholesterol, SAA, and IL-6 assays. Renal sections were used for histological assessments. The lipid accumulation in kidney was evaluated by Oil Red O staining and quantita-tive analysis. The mRNA expression and protein expression of TGF-β1, Collagen I and Collagen IV, FN, a-SMA were analyzed by RT-PCR and IHC.
Results: Blood levels of SAA, IL-6 were lower (P<0.05), while TC, LDL-C and HDL-C were not different in the D1 group, Compared to B2 group. Meanwhile, lipid accumulation in the kidney was less and renal function was better (P<0.05). PAS, Masson and HE staining demonstrated Atorvastatin therapy attenuated massive structural changes. Compared to B2 group, there were decreased gene and protein expression of Collagen I, Collagen IV, TGF-β1, a-SMA, and FN in the Atorvastatin therapy group (P<0.05).
Conclusion: The beneficial effect of Atorvastatin might be mediated by the effect of anti-inflammatory action through a reduction TGF-β1 ex-pression independent of the lipid-lowering effect and cellular uptake of SR-A,CD36.
PART 5: STATIN RESISTANCE UNDER INFLAMMATION STRESS
Objective: Our previous vitro study has demonstrated that inflamma-tion can lead statin resistance in human hepatoma cell line.This part was design to explore if there was statin resisitance in vivo for Eno-protective Effects of Atorvastatin under inflammation stress.
Methods: Two doses of atorvastatin were administered in SR-A/CD36/ApoE triple KO mice which were fed with high fat plus in-flammtion, 2mg/kg/d (D2) and 10mg/kg/d (D3), respectively. Terminal blood samples were taken for Scr, BUN, TC, TG, LDL-C, HDL-C, SAA and IL-6 assays. Renal sections were used for histological and IHC assessments. Renal histopathology was quantified using GSI, TII. The lipid accumulation in kidney was evaluated by Oil Red O staining and quantitative analysis. The mRNA of TGF-β1, Collagen I and Collagen IV, FN, a-SMA, were analyzed by RT-PCR.
Results: In the inflammatory state, compared to C2 group, D2, D3 group could not effectively reduce the the serum lipid levels (P>0.05).Compared to C2 group, D2 group could not obviously reduce kidney deposition of cholesterol and Scr (P>0.05), and improve the kidney deterioration, while D3 group could reduce kidney tissue cholesterol depo- sition and ameliorate the pathological changes of kidney obviously (P<0.05). Compared to C2 group, the gene expression of Collagen I, Collagen IV was not decreased in D2 group (P>0.05), while D3 group could significantly reduced the TGF-β1, Collagen I and Collagen IV, FN, a-SMA gene expres-sion (P<0.05).
Conclusion: Atorvastatin may not as effective on renal protection as it is in the absence of inflammtion. To achieve the same effect, the dose of Atorvastatin should increase accordingly.The potential mechanisms deserve futher exploration.
PART 6: MCP-1 GENE POLYMORPHISM AND MCP-1 EX-PRESSION IN CHONGQING HAN CHILDREN WITH TU-BERCULOSIS
Objective: The aims of this study were to evaluate whether the presence of–2518A/G polymorphism in the distal regulatory region of the MCP-1 was associated with tuberculosis (TB) in Chongqing Han population and to find whether it has a significant impact on the pediatric patient.
Method: One hundred children and one hundred adults with TB and 200 healthy controls of comparable age were screened for genotype by PCR-sequence-specific primer (SSP) method. MCP-1 levels in the plasma were detected by ELISA.
Result: (1) The -2518GG genotypes was associated with increased TB susceptibility (P<0.05). (2) The odds of developing TB in genotypes GG were higher than those in homozygous AA, and the risk was higher in chil-dren than in adult (P<0.05). (3) Cases of homozygous GG had the highest plasma levels of MCP-1, which increased the likelihood of developing TB. Furthermore, higher levels were observed in children than in adults (P<0.05).
Conclusion: These findings suggest that persons bearing the MCP-1 genotype GG produce high concentrations of MCP-1, which increases the risk of active TB infection in Chongqing Han people. These findings are more significant in child patients than in adult patients with TB.
目的:探讨炎症是否加重脂质诱导的肾脏的损伤。
方法:采用雄性C57BL/6小鼠,将小鼠随机分为三组:普通饮食组(A1)、高脂饮食组(B1)、高脂+炎症组(由皮下注射0.5ml 10%酪蛋白(Casein)/隔天诱导)(C1)。14周后处死,检测血清中IL-6、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)的水平。油红“O”染色及酶法检测肾组织内脂质沉积情况。HE、PAS、Masson染色观察肾脏形态学改变。(Real-time PCR,RT-PCR)实时荧光定量PCR和免疫组化技术(IHC)分别检测肾组织转化生长因子(TGF-β1)、纤维连接蛋白(FN)、I型胶原(Collagen I)、IV型胶原(Collagen IV)的基因与蛋白表达。
结果:与B1组比较,C1组血清中的IL-6显著升高(P<0.05),表明皮下注射Casein成功建立了系统慢性炎症小鼠模型。与A1组相比,B1组TC、LDL-C显著升高(P<0.01)。与B1组比较,C1组的血清的TC、LDL-C水平显著下降(P<0.05),而肾脏组织总胆固醇、胆固醇酯水平显著升高(P<0.05),病理学检测发现系膜细胞的增生和系膜基质的扩张,GSI显著增高(P<0.05)。RT-PCR及免疫组化检测发现炎症上调了TGF-β1、Collagen I、Collagen IV的表达(P<0.05)。
结论:炎症状态下,血浆胆固醇水平并不与肾脏损害呈正相关。炎症促进血清里的胆固醇不断进入肾脏组织细胞,降低了血清中的脂质水平,加重了脂质诱导的肾脏损伤。
第二部分:SREBP-LDLr/HMGCoA还原酶途径在炎症加重脂质诱导肾脏损伤的作用
目的:探讨胆固醇调节元件结合蛋白裂解蛋白(SCAP)-胆固醇调节元件结合蛋白2(SREBP2)-低密度脂蛋白受体(LDLr)/羟甲基戊二酸单酰CoA还原酶(HMGCoA还原酶)途径在炎症加重脂质诱导的肾脏损伤中的作用。
方法:在第一部分研究的动物模型上,RT-PCR检测SCAP,SREBP2、HMGCoA还原酶和LDLr基因水平,Western blot(WB)检测相应蛋白表达量。有相关趋势的变量采用Pearson相关分析。
结果:与B2组相比,C2组SCAP,SREBP2、HMGCoA还原酶和LDLr基因与蛋白表达显著上调(P<0.05),并且HMGCoA还原酶和LDLr蛋白的表达与肾脏组织沉积的胆固醇酯(CE)成正相关(P<0.05)。
结论:炎症可以通过上调SCAP-SREBP2-LDLr/HMGCoA还原酶的表达,促进胆固醇的合成和摄取,加重了脂质在肾脏的沉积,加重诱导了肾脏的损伤。
第三部分:炎症加重SR-A/CD36/ApoE三敲小鼠脂质诱导的肾脏损伤及主要机制
目的:应用SR-A/CD36/ApoE三敲除小鼠模型,旨在探讨清道夫受体CD36、SR-A及LDLr在炎症加重脂质介导的肾脏损伤的作用。
方法:C57BL/6来源的雄性SR-A/CD36/ApoE三敲除小鼠,将小鼠随机分为三组:普通饮食组(A2)、高脂饮食组(B2)、高脂+炎症组(C2)。14周后处死,检测血清中淀粉样蛋白(SAA)、IL-6、肌酐(Scr)、尿素氮(BUN)、TC、TG、LDL-C、和HDL-C水平。检测尿蛋白/尿肌酐的水平。油红“O”染色及酶法检测肾组织内脂质沉积情况。HE,PAS,Masson方法观察肾脏形态学改变。RT-PCR技术检测肾组织TGF-β1、FN、Collagen I、Collagen IV、a肌动蛋白(a-SMA)、LDLr、SREBP2、SCAPmRNA表达。IHC与WB技术检测TGF-β1、FN、Collagen I、Collagen IV、a-SMA、LDLr、SREBP2-N、SCAP蛋白表达。
结果:C2组血清炎症因子SAA,IL-6显著高于B2及A2组,表明炎症模型成功建立(P<0.05)。C2组血清中TC、LDL-C、HDL-C显著低于B2组(P<0.05),肾脏胆固醇,胆固醇酯的沉积却显著升高(P<0.05),血清Scr,BUN,尿蛋白/尿肌酐显著升高(P<0.05)。肾脏病理学检查发现C2组肾小球基底膜增厚,肾小管上皮细胞变性萎缩,蛋白管型及炎症细胞浸润等改变,GSI、TII显著高于B2组(P<0.05)。进一步检测发现炎症上调了肾脏Collagen I、Collagen IV、a-SMA、TGF-β1、FN mRNA与蛋白的表达(P<0.05)。炎症还显著促进了LDLr、SCAP、SREBP2mRNA及蛋白质的表达(P<0.05)。
结论:炎症可以通过SREBP2-SCAP-LDLr途径而非CD36/SR-A途径促进了脂质从血清向肾脏的积聚,加重了脂质诱导的肾脏损害。
第四部分:阿托伐他汀非依赖降血脂的肾脏的保护作用
目的:探讨阿托伐他汀的肾脏保护作用及潜在机制。
方法:在第三部分实验的同时,采用SR-A/CD36/ApoE三敲除小鼠设立高脂饮食+2mg/kg/d阿托伐他汀(D1)组,以A1、A2组为对照,B2组为模型组。检测血清IL-6、SAA的水平及脂质水平。油红“O”染色及酶法检测肾组织内脂质沉积情况。HE,PAS,Masson染色观察肾脏形态学改变。RT-PCR与IHC分别检测肾组织TGF-β1、FN、Collagen I、Collagen IV、a-SMA的基因与蛋白表达。
结果:与B2组比较,D1组显著减少了肾脏组织胆固醇、胆固醇酯沉积(P<0.05),显著改善了蛋白尿与肾功能(P<0.05),但是血清中的TC、LDL-C水平无显著的降低(P>0.05)。与B2组比较,D1组可以显著减少高脂饮食诱导的肾脏组织系膜细胞的增生,系膜基质的沉积等病理改变,GSI显著降低(P<0.05)。进一步检测发现D1组显著降低了肾脏组织TGF-β1的基因与蛋白表达(P<0.05),进而显著降低FN、Collagen I、Collagen IV、a-SMA的基因与蛋白表达(P<0.05)。
结论:阿托伐他汀可以不依赖于降血脂,而是通过降低肾脏组织TGF-β1,独立于SRA、CD36受体途径而发挥肾脏保护作用。
第五部分:炎症应激导致他汀抵抗作用
目的:本课题组体外实验已经证明炎症可以导致肝脏细胞对他汀药物的抵抗,本部分将从体内实验进一步探讨炎症反应是否影响阿托伐他汀的肾脏保护作用。
方法:在第三部分实验的同时,对高脂+炎症模型的小鼠加用阿托伐他汀2mg/kg/d(D2)和10mg/kg/d(D3)干预实验,以A2、D1、B2、C2组为对照,酶法检测血清的TC、LDL-C、TG、HDL-C水平与SAA、IL-6水平。HE、PAS、Masson染色方法观察肾脏形态学改变,酶法及油红“O”染色检测肾脏组织中胆固醇的沉积。RT-PCR检测肾组织TGF-β1、FN、Collagen I、Collagen IV、a-SMA的基因表达。
结果:与C2组对比,D2、D3组不能有效降低血脂水平(P>0.05)。与B2比较,D3组可以显著降低血脂水平(P<0.05)。与C2组对比,D2组不能显著的降低肾脏组织胆固醇的沉积、血清肌酐水平(P>0.05)及改善肾脏病理结构的损伤,D3组可显著降低肾脏组织胆固醇的沉积及改善肾脏的病理(P<0.05)。并且,D2组不能显著降低Collagen I、Collagen IV基因的表达(P>0.05),而D3组能显著降低FN、Collagen I、Collagen IV、a-SMA所有基因的表达(P<0.05)。
结论:炎症影响阿托伐他汀肾脏保护作用的疗效,在炎症环境中要达到相同效果需要增大剂量。而导致这个现象的潜在机制值得进一步探讨。
第六部分:重庆汉族儿童单核细胞趋化蛋白-1基因多态性及表达水平与结核病易感性的关系
目的:探讨MCP-1基因启动子区2518A/G多态性、血清MCP-1蛋白表达水平与结核病的相关关系。
方法:研究对象为100例儿童结核病、100例成人结核病以及相应的200例健康对照。序列特异性引物PCR(PCR-SSP)技术检测MCP-1基因启动子区2518A/G多态性。ELISA方法测定相应不同基因型患者和对照血清MCP-1水平。
结果:(1)总体结核病组2518GG基因型频率为65%,明显高于相应的健康对照组(27%)(P<0.05);(2)MCP-1基因启动子区2518位点GG基因型患结核病机率高于AA基因型,且儿童GG基因型发病的危险性高于成人GG基因型(P<0.05);(3)2518 GG基因型的MCP-1水平高于AA基因型和AG基因型。结核组高于正常组,儿童组高于成人组(P<0.05)。
结论:在中国重庆地区汉族人中,MCP-1-2518位GG基因型作为结核病可能的危险因素,在儿童结核病的发病中占有更重要的地位。
PART 1: INFLAMMATORY STRESS EXACERBATES LIPID MEDIATED RENAL INJURY
Objective:The aim of this part was to observe the influence of in-flammation on lipid metabolism disturbance and the progression of renal injury.
Methods:C57BL/6 mice were randomized into normal diet (A1), high fat diet (B1) and high fat diet plus casein injection (C1) (induce inflamma-tion) groups. Animals were sacrificed after 14 weeks, terminal blood sam-ples were taken for cholesterol (TC), triglycerides (TG), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and interleukin-6 (IL-6) assays. Red O stain and intracellular cholesterol concentration assay were performed. The morphological changes of kidney were examied by HE, PAS, Masson staining. The mRNA levels and protein expression of transforming growth factor-β(TGF-β1), collagen type I (Collagen I) and type IV (Collagen IV), Fibronectin (FN) were determined by Real-Time Polymerase Chain Reac-tion (RT-PCR) and immunohistochemistry (IHC) assessments.
Results: Blood IL-6 levels were higher, while TC and LDL-C were lower in the C1 group compared to B1 group (P<0.05). Lipid accumulation in the kidney was more extensive in C1 group despite lower blood lipid levels by ORO staining and quantitative analysis (P<0.05). PAS, Masson and HE staining demonstrated casein injection induced structural changes characterized by mesangial expansion in the kidney. The GSI was signifi-cantly higher in C2 group than those of other group (P<0.05). These ab-normalities were associated with increased gene and protein expression of Collagen I, Collagen IV, and TGF-β1.
Conclusions: Low blood cholesterol levels may be associated with high risk for chronic renal injury under inflammatory stress. Inflammation exacerbates lipid accumulation in kidney by diverting lipid from plasma to kidney.
PART 2: THE ROLE OF SREBP2/LDLR/ HMG-COA REDUC-TASE PATHWAY IN INFLAMMATORY STRESS EXACER-BATES LIPID MEDIATED RENAL INJURY
Objective: To explore the role of the sterol regulatory element binding protein cleavage protein (SCAP)-sterol regulatory element binding protein 2 (SREBP2)-low density lipoprotein receptor (LDLr) / 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) pathways in the process of inflammation stress exacerbating lipid mediated renal injury.
Methods: On the basis of part I, the genes of LDLr, SREBP2, SCAP, HMGCoA reductase involved in cholesterol negative feedback pathways were determined by RT-PCR and western-blotting (WB) as well. Some variables were analysis by Pearson correlation assesment.
Results: The mRNA of SCAP, SREBP2, LDLr, and HMGCoA reduc-tase as well as protein levels were markedly enhanced in C1 group com-pared with B1 group (P<0.05). Casein injection increased LDLr, HMGCoA reductase gene and protein expression in the kidney, probably by disrupting the intracellular cholesterol sensor, regulatory function of SREBP cleavage activating protein (SCAP). Futher, the protein level of HMGCoA reductase and LDLr was positively related to CE deposition in kidney (P<0.05).
Conclusion: Inflammation possibly exacerbates lipid induced-renal injury through the SCAP-SREBP2-LDLr/HMGCoA reductase pathways by abnormal cholesterol synthesising and uptaking.
PART 3: INFLAMMATORY STRESS EXACERBATES LIPID MEDIATED RENAL INJURY IN SR-A/CD36/APOE TRIPLE KNOCK-OUT TRIPLE-KNOCKOUT MICE
Objectives: This study was designed to investigate whether inflam-matory stress exacerbates lipid accumulation in lipid-mediated glomerular injury and, thereby exacerbating the progression of renal injury by non–scavenger receptor–mediated pathways in vivo.
Methods: Male SR-A/CD36/ApoE triple Knock-out (KO) mice were randomly divided into normal diet (A2), high fat diet (B2) and high fat diet plus inflammation groups (C2). Animals were sacrificed after 14 weeks, terminal blood samples were taken for creatinine (Scr), urea nitrogen (BUN), TC, TG, and LDL-C, HDL-C, amyloid A (SAA) and IL-6 assays. Renal sections were used for histological and IHC assessments. Renal histopa-thology was quantified using a glomerulosclerosis index (GSI) and a tubu-lointerstitial injury index (TII). The lipid accumulation in kidney was evaluated by Oil Red O staining and quantitative analysis. The mRNA and protein expression of TGF-β1, Collagen I, Collagen IV, FN, a-smooth mus-cle actin (a-SMA), SREBP2, SCAP, LDLr were analyzed by RT-PCR and WB analysis.
Results: Blood levels of SAA and IL-6 were higher (P<0.05), while TC, LDL-C and HDL-C were lower in the C2 group compared to B2 group (P<0.05). Meanwhile, lipid accumulation in the kidney was more extensive in C2 group despite lower blood lipid levels (P<0.05). Casein injection ex-acerbated renal function failure and proteinuria compared to B2 group (P<0.05). Casein injection induced massive structural changes. The GSI and TII were significantly higher in C2 group than those of B2 group. These abnormalities were associated with increased gene and protein expression of Collagen I, Collagen IV, TGF-β1, a-SMA, and FN. Further analysis showed that casein injection increased LDLr, SREBP2, and SCAP gene and protein expression in the kidney.
Conclusions: Non scavenger receptor-mediated alternative atherogenic pathways are operational, and SCAP-SREBP2-LDLr pathway may be the dominant mechanism for inflammatory stress exacerbating lipid mediated renal Injury.
PART 4: ENO-PROTECTIVE EFFECTS OF ATORVASTATIN INDEPENDENT OF CHOLESTEROL LOWERING
Objective: This part was to investigate whether Atorvastatin de-creased renal lipid accumulation and renal injury independent of the lipid-lowering effect.
Methods: Male SR-A/CD36/ApoE triple KO mice were randomly as- signed to receive high fat diet plus Atorvastatinn treatment group (D1) (2mg/kg/d), other groups of A1, A2 as control groups and B2 as model group. Terminal blood samples were taken for cholesterol, SAA, and IL-6 assays. Renal sections were used for histological assessments. The lipid accumulation in kidney was evaluated by Oil Red O staining and quantita-tive analysis. The mRNA expression and protein expression of TGF-β1, Collagen I and Collagen IV, FN, a-SMA were analyzed by RT-PCR and IHC.
Results: Blood levels of SAA, IL-6 were lower (P<0.05), while TC, LDL-C and HDL-C were not different in the D1 group, Compared to B2 group. Meanwhile, lipid accumulation in the kidney was less and renal function was better (P<0.05). PAS, Masson and HE staining demonstrated Atorvastatin therapy attenuated massive structural changes. Compared to B2 group, there were decreased gene and protein expression of Collagen I, Collagen IV, TGF-β1, a-SMA, and FN in the Atorvastatin therapy group (P<0.05).
Conclusion: The beneficial effect of Atorvastatin might be mediated by the effect of anti-inflammatory action through a reduction TGF-β1 ex-pression independent of the lipid-lowering effect and cellular uptake of SR-A,CD36.
PART 5: STATIN RESISTANCE UNDER INFLAMMATION STRESS
Objective: Our previous vitro study has demonstrated that inflamma-tion can lead statin resistance in human hepatoma cell line.This part was design to explore if there was statin resisitance in vivo for Eno-protective Effects of Atorvastatin under inflammation stress.
Methods: Two doses of atorvastatin were administered in SR-A/CD36/ApoE triple KO mice which were fed with high fat plus in-flammtion, 2mg/kg/d (D2) and 10mg/kg/d (D3), respectively. Terminal blood samples were taken for Scr, BUN, TC, TG, LDL-C, HDL-C, SAA and IL-6 assays. Renal sections were used for histological and IHC assessments. Renal histopathology was quantified using GSI, TII. The lipid accumulation in kidney was evaluated by Oil Red O staining and quantitative analysis. The mRNA of TGF-β1, Collagen I and Collagen IV, FN, a-SMA, were analyzed by RT-PCR.
Results: In the inflammatory state, compared to C2 group, D2, D3 group could not effectively reduce the the serum lipid levels (P>0.05).Compared to C2 group, D2 group could not obviously reduce kidney deposition of cholesterol and Scr (P>0.05), and improve the kidney deterioration, while D3 group could reduce kidney tissue cholesterol depo- sition and ameliorate the pathological changes of kidney obviously (P<0.05). Compared to C2 group, the gene expression of Collagen I, Collagen IV was not decreased in D2 group (P>0.05), while D3 group could significantly reduced the TGF-β1, Collagen I and Collagen IV, FN, a-SMA gene expres-sion (P<0.05).
Conclusion: Atorvastatin may not as effective on renal protection as it is in the absence of inflammtion. To achieve the same effect, the dose of Atorvastatin should increase accordingly.The potential mechanisms deserve futher exploration.
PART 6: MCP-1 GENE POLYMORPHISM AND MCP-1 EX-PRESSION IN CHONGQING HAN CHILDREN WITH TU-BERCULOSIS
Objective: The aims of this study were to evaluate whether the presence of–2518A/G polymorphism in the distal regulatory region of the MCP-1 was associated with tuberculosis (TB) in Chongqing Han population and to find whether it has a significant impact on the pediatric patient.
Method: One hundred children and one hundred adults with TB and 200 healthy controls of comparable age were screened for genotype by PCR-sequence-specific primer (SSP) method. MCP-1 levels in the plasma were detected by ELISA.
Result: (1) The -2518GG genotypes was associated with increased TB susceptibility (P<0.05). (2) The odds of developing TB in genotypes GG were higher than those in homozygous AA, and the risk was higher in chil-dren than in adult (P<0.05). (3) Cases of homozygous GG had the highest plasma levels of MCP-1, which increased the likelihood of developing TB. Furthermore, higher levels were observed in children than in adults (P<0.05).
Conclusion: These findings suggest that persons bearing the MCP-1 genotype GG produce high concentrations of MCP-1, which increases the risk of active TB infection in Chongqing Han people. These findings are more significant in child patients than in adult patients with TB.
引文
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