Zhang Qing, Ji Yongqiang, Lv Wei, He Tianwei, Wang Jianping
a Department of Nephrology , Yantai Yuhuangding Hospital, Qingdao University Medical School , Yantai , Shandong , China.
Ren Fail. 2016;38(1):124-30. doi: 10.3109/0886022X.2015.1105024. Epub 2015 Oct 29.
Diabetic nephropathy is one of the most common chronic complications of diabetes with poor efficacy of clinical treatment. This study investigated the protective effects of leflunomide, a new immunosuppressant, on tubulointerstitial lesions in a rat model of diabetic nephropathy. Diabetes was induced with streptozotocin (STZ, 50 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 8 weeks with low (5 mg/kg) and high dose (10 mg/kg) of leflunomide, and benazepril hydrochloride (4 mg/kg) as a positive control. In diabetic rats, the 24-h urine volume, urine protein and microalbumin, blood creatinine and urea nitrogen significantly increased, which were attenuated by leflunomide treatment in a dose-dependent manner (all p < 0.05). The increase of kidney weight/body weight and the histopathological findings of tubulointerstitial lesion in diabetic rats were mitigated by leflunomide treatment. Immunohistochemistry study and real-time polymerase chain reaction results demonstrated that osteopontin (OPN), transforming growth factor beta 1 (TGF-β1), α-smooth muscle actin and CD68 expression in the renal tubulointerstitial region were significantly increased in the diabetic rats, while these increases were inhibited by leflunomide treatment. These findings suggest that leflunomide protects the kidney injury of diabetic rats might through its inhibition of OPN/TGF-β1 mediated extracellular matrix deposition and tubulointerstitial fibrosis, as well as its inhibition on tubular epithelial-myofibroblast transdifferentiation.
糖尿病肾病是糖尿病最常见的慢性并发症之一，临床治疗效果不佳。本研究探讨了新型免疫抑制剂来氟米特对糖尿病肾病大鼠模型肾小管间质损伤的保护作用。采用链脲佐菌素（STZ，50mg/kg）腹腔注射诱导雄性Wistar大鼠患糖尿病。STZ注射两周后，糖尿病大鼠每天接受低剂量（5mg/kg）和高剂量（10mg/kg）来氟米特治疗8周，并用盐酸贝那普利（4mg/kg）作为阳性对照。糖尿病大鼠的24小时尿量、尿蛋白和微量白蛋白、血肌酐和尿素氮显著增加，而来氟米特治疗以剂量依赖方式减轻了这些指标的变化（所有p<0.05）。来氟米特治疗减轻了糖尿病大鼠肾重/体重的增加以及肾小管间质损伤的组织病理学表现。免疫组织化学研究和实时聚合酶链反应结果表明，糖尿病大鼠肾小管间质区域骨桥蛋白（OPN）、转化生长因子β1（TGF-β1）、α平滑肌肌动蛋白和CD68表达显著增加，而来氟米特治疗抑制了这些增加。这些发现表明，来氟米特可能通过抑制OPN/TGF-β1介导的细胞外基质沉积和肾小管间质纤维化，以及抑制肾小管上皮-肌成纤维细胞转分化来保护糖尿病大鼠的肾脏损伤。
