非布司他对高尿酸血症模型大鼠肾小管上皮间质转化的影响

发布时间：2018-05-23 13:32

  本文选题：高尿酸血症 + EMT　； 参考：《南方医科大学》2017年硕士论文

【摘要】：研究背景持续的高尿酸血症(Hyperuricemia,HUA)使尿酸盐堆积引起肾脏病变,称尿酸性肾病。许多慢性肾病(Chronic kidney disease,CKD)有共同的病理过程一肾小管间质纤维化(Renal Inierstitial Fibrosis,RIF),肾小管上皮间质转化(epithelial mesenchyml transition,EMT)被认为是 RIF 的早期表现。肾小管 EMT即肾小管上皮细胞失去表型特征而获得间质细胞表型特征的过程。EMT受多种因素诱导和促发,转化生长因子(TGF-β)是最为重要的诱导因子,在EMT参与胚胎发育、肿瘤转移、器官纤维化中均有非常重要的作用。尿酸(Uricacid,UA)直接刺激肾小管上皮细胞,使E-cadherin的合成减少、a-SMA表达增加,肾小管发生EMT。此外,UA还通过泛素化增加了 E-cadherin的降解,导致肾小管上皮细胞的极性消失。黄嘌呤氧化酶抑制剂(Xanthine oxidase inhibitors,XOI)非布司他能降低UA水平,减轻CKD病情,但缺乏大规模前瞻性临床试验证明。目的观察HUA大鼠肾功能及肾脏结构的变化,探讨UA引起肾小管上皮EMT的可能机制。使用非布司他和苯溴马隆片分别干预治疗,观察并比较两药对HUA大鼠肾小管上皮间质转化的影响,进一步探讨非布司他在预防肾纤维化中的作用。(1)SD大鼠随机分为正常对照组(NC组)、HUA组、非布司他组(FX组)及苯溴马隆组(BN组),每组12只。氧嗪酸钾灌胃建立HUA模型。FX组及BN组在造模的同时给予非布司他(7.2mg/(kg.d))和苯溴马隆(9mg/(kg.d))治疗。(2)检测大鼠血 UA、Scr、BUN、IL-6、Cys-c、TGF-β1、BMP-7 及尿蛋白的水平;HE及Masson染色观察肾组织情况,免疫组化测定E-cadherin、a-SMA、CollageⅢ及 TGF-β1 的表达。结果与NC组对比,各组UA、Scr、BUN、IL-6、Cys-c及TGF-β1水平均升高,BMP-7水平下降,差异均有统计学意义(P0.05或P0.01);第4周时,FX组 Cys-c、IL-6、TGF-β1 水平较 HUA 组明显下降(P0.01);UA 与 IL-6、Cys-c及TGF-β1呈正相关关(r=0.908,P=0.000;r=0.759,P=0.000;r=0.850,P=0.000),与BMP-7呈负相关关系(r=-0.826,P=0.000)。HE染色显示,非布司他治疗明显改善肾损伤;Masson染色提示HUA组肾纤维化程度大于其他三组(P0.01),FX组纤维化缓解优于BN组;免疫组化检测发现,NC组肾组织不表达a-SMA,高表达E-cadherin;FX组与HUA组比较,a-SMA及CollageⅢ明显减少(P0.01),E-cadherin表达增加(P0.01)。结论HUA引起肾小管EMT发生,肾小管上皮细胞的表型转化是在肾间质显著纤维化前发生的;Cys-c较传统的肾功能指标更敏感,可作为早期尿酸性肾损伤的预测指标;非布司他有效地降低UA水平,减少IL-6/TGF-β1的表达,增加BMP-7拮抗TGF-β1的作用,逆转早期纤维化的发生。但非布司他对IL-6/TGF-β1及BMP-7/TGF-β1的具体调控机制需进一步研究。
[Abstract]:Background: hyperuricemia and hyperuricemia (HUAA) cause renal disease caused by accumulation of uric acid, known as uric acid nephropathy. Many chronic kidney disease (CKD) have a common pathological process: renal tubulointerstitial fibrosis (RIF), epithelial mesenchyml transition (EMTT) is considered to be the early manifestation of RIF. Tubule EMT is the process of obtaining the phenotypic characteristics of interstitial cells due to the loss of phenotypic characteristics of renal tubular epithelial cells. TGF- 尾 is the most important inducing factor, and TGF- 尾 is the most important inducer in EMT, which is involved in embryonic development and tumor metastasis. Organ fibrosis plays a very important role. Uricacidy UAA directly stimulated renal tubule epithelial cells, which decreased the expression of E-cadherin and increased the expression of a-SMA in renal tubules. In addition, UA increased the degradation of E-cadherin through ubiquitization, resulting in the disappearance of the polarity of renal tubular epithelial cells. Xanthine oxidase inhibitors (XOI) can reduce UA level and alleviate the condition of CKD, but lack of large scale prospective clinical trials. Objective to observe the changes of renal function and renal structure in HUA rats and to explore the possible mechanism of renal tubular epithelial EMT induced by UA. To observe and compare the effects of the two drugs on renal tubule epithelial interstitial transformation in HUA rats. To further explore the role of fentinastar in the prevention of renal fibrosis, SD rats were randomly divided into normal control group (NC group), control group (n = 12), control group (n = 12) and group B (n = 12). HUA model was established by intragastric administration of potassium oxazinate. FX group and BN group were treated with non-busultadine 7.2mg / kg 路dl and benzbromarone 9 mg / kg 路dX).) the level of Scr-BUNIL-6 Cys-cTGF- 尾 1BMP-7 and urine protein were detected by HE staining and Masson staining. The expression of E-cadherina-SMA Collage 鈪，

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