Wang Yin, Ma Li, Tong Jun-rong, Luo Zheng-mao, He Feng
Institute of Molecular Immunology, School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2008 May;28(5):835-8.
To investigate the protective effect of urokinase on renal interstitial inflammation and fibrosis in rats with chronic cyclosporine A (CsA)-induced nephropathy.
Male SD rats were fed on low salt diet (0.05% sodium) for 7 days and randomized into 4 groups for treatment with CsA, CsA+continuous low-dose uPA (U2), intermittent CsA+ high-dose uPA (U6) or vehicle (control group). In the former 3 groups, the rats were subjected to daily intragastric administration of CsA (25 mg/kg) for 4 weeks to establish CsA-induced chronic nephropathy model, and those in U2 and U6 groups were given uPA at 2000 U/kg daily or at 6000 U/kg every 3 days, respectively. Four weeks after the treatment, the renal function and 24-h proteinuria were assessed, and Masson staining was used for examining fibrin deposition. Semi-quantitative immunohistochemical staining was employed for evaluation of ED-1-positive cells, urokinase-type plasminogen activator (uPA) and transforming growth factor-beta1 (TGF-beta 1).
Four weeks after the treatment, the CsA-treated rats showed significantly elevated serum creatinine (Scr), blood urea nitrogen (BUN) and increased urine proteins. Continuous administration of low-dose uPA resulted in significantly reduced Scr, BUN and 24-h urine protein excretion, while intermittent high-dose uPA treatment did not produce such changes. CsA increased fibrin deposition, total number of macrophages in renal interstitium and TGF-beta1 expression in the renal tissue, which were significantly reduced in U2 group (P<0.05) but not in U6 group (P>0.05).
Continuous administration of low-dose uPA may reduce interstitial fibrin deposition and alleviate renal interstitial inflammation in rats with chronic CsA nephropathy, possibly by reducing the number of macrophages and TGF-beta1 expression in the renal tissue.
探讨尿激酶对慢性环孢素A（CsA）诱导的大鼠肾病肾间质炎症和纤维化的保护作用。
雄性SD大鼠给予低盐饮食（0.05%氯化钠）7天，随机分为4组，分别用CsA、CsA+持续低剂量尿激酶原（U2）、间歇CsA+高剂量尿激酶原（U6）处理或作为对照（对照组）。在前3组中，大鼠每天灌胃给予CsA（25mg/kg）4周以建立CsA诱导的慢性肾病模型，U2组和U6组大鼠分别每天给予2000U/kg尿激酶原或每3天给予6000U/kg尿激酶原。处理4周后，评估肾功能和24小时蛋白尿，并用Masson染色检查纤维蛋白沉积。采用半定量免疫组化染色评估ED-1阳性细胞、尿激酶型纤溶酶原激活剂（uPA）和转化生长因子-β1（TGF-β1）。
处理4周后，CsA处理的大鼠血清肌酐（Scr）、血尿素氮（BUN）显著升高，尿蛋白增加。持续给予低剂量uPA可使Scr、BUN和24小时尿蛋白排泄显著降低，而间歇高剂量uPA处理未产生此类变化。CsA增加了肾间质纤维蛋白沉积、肾间质巨噬细胞总数和肾组织中TGF-β1表达，U2组这些指标显著降低（P<0.05），而U6组未降低（P>0.05）。
持续给予低剂量uPA可能通过减少肾组织中巨噬细胞数量和TGF-β1表达，降低慢性CsA肾病大鼠的间质纤维蛋白沉积，减轻肾间质炎症。
