炎症因子与高尿酸血症性肾病大鼠的关系及药物干预研究

Study on inflammatory factors with uric acid nephropathy and drug intervention in rats

目的研究尿激酶纤维蛋白溶酶原激活物(u PA)对高尿酸血症性肾病大鼠的保护作用,进而探讨其治疗高尿酸血症性肾病大鼠的机制。方法采用腺嘌呤+盐酸乙胺丁醇灌胃法建立大鼠高尿酸血症性肾病模型,将实验动物随机分为u PA干预组、别嘌呤醇干预组和模型组,并设立对照组。于实验第6﹑10周时间点采用酶联免疫吸附试验法(ELISE)检测大鼠肿瘤坏死因子-α(TNF-α)、血清细胞间黏附分子-1(ICAM-1)的表达,磺柳酸比浊法观察24 h尿蛋白定量的变化,同时分析大鼠临床表现,免疫组化法测定肾脏组织转化生长因子-β1(TGF-β1)的表达。结果 (1)造模成功后干预组、模型组血清TNF-α、ICAM-1、肾脏组织TGF-β1值均高于对照组,差异具有统计学意义(P<0.05);(2)u PA、别嘌呤醇干预组治疗10周后与模型组比较TNF-α、ICAM-1值有下降,差异具有统计学意义(P<0.05),但两组之间比较差异无统计学意义(P>0.05);(3)u PA、别嘌呤醇干预组治疗10周后肾组织中TGF-β1(0.21±0.03、0.21±0.04)的浓度及肾间质纤维化程度(2.63±0.21、2.71±0.13)等指标与模型组(0.39±0.01、3.86±0.73)比较亦均有下降(P<0.05)。结论 (1)TNF-α、ICAM-1、TGF-β1可能与高尿酸血症性肾病的发生、发展及预后相关,可成为高尿酸血症性肾脏病变的预测因子;(2)u PA治疗高尿酸血症性肾病的机制可能是通过抑制炎症因子的表达,直接或间接影响系膜细胞增殖和系膜基质增生。

Objective To investigate the protective effects and mechanisms of urokinase(u PA) on high uric acid nephropathy in rats. Methods Adenine+ethambutol hydrochloride by gastric method was used to establish the rat model of high uric acid nephropathy, experimental animals were randomly divided into u PA treated interfering group, the allopurinol treated interfering group and model group, and the establishment of the control group. In the experiment after 6, 10 weeks, the serous concentrations of TNF-α and ICAM-1 were measured by enzyme linked immunosorbent assay(ELISA), and 24 h urine protein content was determined by sulfosalicylic acid methods. The levels of TGF-β1 in the renal tissues were detected by immunohistochemical staining, meanwhile analyzed clinical manifestation of rats. Results The level of serum TNF-α, ICAM-1 and kidney tissue TGF-β1 in treated and model groups were higher than in normal group, the difference was statistically significant(P<0.05); After treatment for 10 weeks, the serum levels of TNF-α, ICAM-1 were all decreased compared with model group, the difference was statistically significant(P<0.05), but there was no statistically significant difference compared between these two treated interfering groups(P>0.05); After treatment for 10 weeks, the levels of kidney tissue TGF-β1(0.21±0.03, 0.21±0.04) and renal interstitial fibrosis indexes(2.63±0.21, 2.71±0.13) in u PA treated interfering group and allopurinol treated interfering group were also decreased compared with model group(0.39±0.01, 3.86±0.73)(P<0.05). Conclusion The plasma levels of ICAM-1, TNF-α, TGF-β1 may be correlated to the occurence, development and prognosis of high uric acid nephropath, becoming predicted factors of high uric acid nephropath; The therapeutic mechanism of u PA with high uric acid nephropath lies probably in the inhibition of these factors expression, thus directly or indirectly affecting the proliferation of mesangial cells and mesangial matrix.