中文摘要：

目的：研究曲尼斯特延缓糖尿病肾病肾间质纤维化的作用及机制。方法：建立糖尿病肾病（DKD）大鼠模型：SD大鼠随机分为正常对照组（n=6）、DKD模型组（n=8）、曲尼斯特低剂量（n=8）和高剂量治疗组（n=8）。采用高糖高脂饲料喂养联合低剂量STZ注射构建大鼠DKD模型。成模后，分别予以曲尼斯特200mg／（kg．d）（曲尼斯特低剂量组）和400mg／（kg．d）（曲尼斯特高剂量组）分2次灌胃。于第8周末处死大鼠，收集大鼠24h尿液测24h尿白蛋白排泄量，收集血测。肾功能及血白蛋白；取部分肾组织置于4％中性甲醛溶液中固定，采用免疫组织化学检测肾组织补体C3a受体（C3aR），E-钙黏附蛋白（epithelial cadherin，E—Cadherin），a—SMA，纤维连接蛋白（fibronectin，FN），I型胶原蛋白（collagen I，ColI），干细胞生长因子（stem cell factor，SCF）和干细胞因子受体c-kit）的表达以及分布；Western印迹检测肾组织E—cadherin，a-SMA，FN，ColI，SCF和c-kit蛋白的表达；RT-PCR检测肾组织FN，ColI，SCF，c-kit mRNA的表达。结果：曲尼斯特能抑制肥大细胞在DKD大鼠肾组织的浸润；DKD模型组肾小管上皮细胞E-cadherin的表达较正常对照组减少，并可见a-SMA表达，曲尼斯特可一定程度逆转这一过程；与正常对照组比较，DKD模型组肾小管间质区域ColI和FN的表达增加，曲尼斯特能剂量依赖性地抑制col I和FN的表达；DKD大鼠肾组织SCF，c-kit蛋白及mRNA表达增加；肾组织SCF，c-kit蛋白表达与肥大细胞浸润程度及肾小管间质FN，ColI蛋白的表达呈显著正相关。曲尼斯特能抑制SCF，c—kit mRNA及蛋白的表达（P〈0．05）。结论：肥大细胞参与了DKD大鼠肾间质纤维化的发生发展，曲尼斯特可能通过阻断SCF／c—kit信号通路，抑制肥大细胞的募集而逆转DKD大鼠肾小管上皮细胞的EMT，抑制肾间质纤维化。

英文摘要：

Objective： To determine the role and mechanism of tranilast preventing the progression of tubulointerstilial fibrosis in diabetic kidney disease （DKD）. Methods： Sprague-Dawley rats were randomly divided into a control group （n=6）, DKD model group （n=8）, low dose tranilast group [200 mg/（kg.d）, n=8], and high dose tranilast group [400 mg/（kg.d）, n=8]. Tranilast was administered daily after the model was built. Rats were sacrificed at day 56, 24 hour urine was collected to measure 24-hour urine albumin excretion, and blood was collected to determine the renal function and serum albumin. Then the kidneys were harvested and subjected to studies. The expression of C3aR, E-cadherin, a-SMA, fibronectin（FN）, collagen I （Col I）, stem cell factor （SCF） and c-kit were detected by immunohistochemical staining respectively. The expression of E-cadherin, a-SMA, FN, Col I, SCF and c-kit protein was analyzed by Western blot, and the expression of FN, Col I, SCF and c-kit mRNA was examined by RT-PCR. Results： Tranilast can inhibit the infiltration of mast cells in the kidneys of DKD rats. The expression of a-SMA in the kidneys of DKD rats inereased significantly （P〈0.05）, while the expression of E-cadherin decreased （P〈0.05）. Tranilast increased the expression of E-cadherin and decreased the expression of a-SMA in the prophase of DKD dose dependently. The expressions of FN and Col I were increased in the tubulointerstitial fields in DKD model rats （P〈0.05）. After the tranilast treatment, these changes were relieved to a certein degree （P〈0.05）. The expression of SCF and c-kit in the tubular and interstitial tissue was slight, The increased expressions of SCF and c-kit protein and mRNA in DKD model rats were downregulated by tranilat （P〈0.05）. The expressions of SCF and c-kit were positively correlated with the infiltration degree of mast cells and the expressions of FN, Col I. Conclusion： Mast cells participate in and aggravate the renal tubulointerstitial fib