Department of Nephrology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Str, Nangang District, Harbin, People's Republic of China.
Endocrine. 2013 Dec;44(3):666-74. doi: 10.1007/s12020-013-9907-0. Epub 2013 Mar 7.
Tubulointerstitial fibrosis is the final common pathway to diabetic nephropathy. However, only a few drugs are responsible for this pathologic process. We investigated the possible effect of deferiprone (iron chelator) treatment on experimental diabetic nephropathy (DN) rats, as well as the mechanisms involved in this process. Diabetic nephropathy was induced in rats by feeding on high-carbohydrate-fat food and injecting streptozotocin. After 20 weeks of deferiprone treatment, tubulointerstitial morphology was detected by staining with hematoxylin-eosin and Masson's trichrome. Tubulointerstitial fibrosis was measured using the point-counting technique. Biochemical parameters including fasting glucose, insulin resistance (IR), serum iron, ferritin, transferrin saturation (TS), and urinary albumin/creatinine ratio (UA/C) were detected in diabetic nephropathy models. Semiquantitative RT-PCR, western blot, and immunohistochemistry were utilized for evaluating mRNA and protein levels of tenascin C, fibronectin 1 (Fn1), TGF-β1, and collagen IV in nephridial tissue, respectively. Malonialdehyde (MDA) and superoxide dismutase (SOD) were determined by pyrogallol and thiobarbituric acid method. Tubulointerstitial fibrosis was significantly ameliorated after deferiprone treatment, and both mRNA and protein expressions of profibrotic factors were inhibited in treatment groups. Meanwhile, high levels of serum iron, ferritin, TS, and UA/C were observed in DN rats. These factors were down-regulated by deferiprone treatment. Furthermore, deferiprone effectively relieved serum IR and regulated oxidative stress process. Our results demonstrated the anti-fibrosis potential and renoprotective effects of deferiprone for diabetic nephropathy, and this process was partially mediated by tenascin C blocking.
肾小管间质纤维化是糖尿病肾病的最终共同途径。然而，只有少数几种药物对此病理过程负责。我们研究了去铁酮（铁螯合剂）治疗对实验性糖尿病肾病（DN）大鼠的可能影响，以及该过程中涉及的机制。通过高碳水化合物-高脂肪饮食喂养和链脲佐菌素注射诱导糖尿病肾病。去铁酮治疗 20 周后，用苏木精-伊红和 Masson 三色染色检测肾小管间质形态。采用点计数技术测量肾小管间质纤维化。在糖尿病肾病模型中检测空腹血糖、胰岛素抵抗（IR）、血清铁、铁蛋白、转铁蛋白饱和度（TS）和尿白蛋白/肌酐比（UA/C）等生化参数。半定量 RT-PCR、western blot 和免疫组织化学分别用于评估肾组织中 tenascin C、纤维连接蛋白 1（Fn1）、TGF-β1 和胶原 IV 的 mRNA 和蛋白水平。通过邻苯三酚和硫代巴比妥酸法测定丙二醛（MDA）和超氧化物歧化酶（SOD）。去铁酮治疗后肾小管间质纤维化明显改善，治疗组纤维化因子的 mRNA 和蛋白表达均受到抑制。同时，DN 大鼠血清铁、铁蛋白、TS 和 UA/C 水平升高。去铁酮治疗可降低这些因子的水平。此外，去铁酮还能有效缓解血清 IR 并调节氧化应激过程。我们的结果表明，去铁酮对糖尿病肾病具有抗纤维化和肾脏保护作用，该过程部分通过阻断 tenascin C 介导。
