Department of Oral Biology, Georgia Health Sciences University, Augusta, GA 30912, United States.
Vascul Pharmacol. 2011 Nov-Dec;55(5-6):149-56. doi: 10.1016/j.vph.2011.07.007. Epub 2011 Jul 23.
Tyrosine kinase inhibition is known to reduce diabetes-induced end-organ damage but the mechanisms remain elusive. We hypothesized that inhibition of tyrosine kinase reduces renal inflammation and injury in streptozotocin-induced diabetes. Male C57BL/6 mice were given daily injections of streptozotocin (45 mg/kg/day, i.p. for 5 days); control animals received the vehicle (citrate buffer). Thereafter, streptozotocin-treated mice were treated with genistein (10 mg/kg, i.p three times a week for 10 weeks, n=8-10/group) or the vehicle (5% DMSO). The streptozotocin-treated mice displayed significant elevation in blood glucose level and decrease in plasma insulin level compared to their vehicle-treated controls. Treatment with genistein reduced blood glucose level (~15%; p<0.05) without a significant effect on plasma insulin level; however, blood glucose remained significantly higher than the control group. The development of diabetes was associated with significant increases in total protein, albumin, nephrin and collagen excretions compared to their controls. In addition, the diabetic mice displayed increased urinary MCP-1 excretion in association with increased renal ICAM-1 expression and apoptotic cells. Furthermore, renal gp91 expression levels and urinary Thio-Barbituric Acid Reactive Substances (TBARs) excretion, indices of oxidative stress, were also elevated in diabetic mice. These changes were associated with increased renal phospho-tyrosine expression and renal phospho-ERK/ERK ratio. Importantly, treatment with genistein reduced all these parameters towards control values. Collectively, the results suggest that the reno-protective effect of genistein likely relates to reduced renal inflammation, oxidative stress and apoptosis in diabetic mice.
酪氨酸激酶抑制已知可减少糖尿病引起的终末器官损伤，但机制仍不清楚。我们假设抑制酪氨酸激酶可减少链脲佐菌素诱导的糖尿病中的肾脏炎症和损伤。雄性 C57BL/6 小鼠每天接受链脲佐菌素（45mg/kg/天，腹腔内注射 5 天）；对照动物接受载体（柠檬酸盐缓冲液）。此后，用染料木黄酮（10mg/kg，腹腔内注射，每周 3 次，共 10 周，n=8-10/组）或载体（5%DMSO）处理链脲佐菌素处理的小鼠。与载体处理的对照相比，链脲佐菌素处理的小鼠的血糖水平显着升高，血浆胰岛素水平降低。用染料木黄酮治疗可降低血糖水平（约 15%；p<0.05），而对血浆胰岛素水平没有显着影响；然而，血糖水平仍显着高于对照组。与对照相比，糖尿病的发展与总蛋白、白蛋白、nephrin 和胶原排泄显着增加有关。此外，糖尿病小鼠的尿液 MCP-1 排泄增加与肾 ICAM-1 表达和凋亡细胞增加有关。此外，糖尿病小鼠的肾 gp91 表达水平和尿液硫代巴比妥酸反应物质（TBARs）排泄增加，氧化应激的指标也升高。这些变化与肾磷酸酪氨酸表达和肾磷酸-ERK/ERK 比值增加有关。重要的是，用染料木黄酮治疗可将所有这些参数降低至对照值。总之，结果表明染料木黄酮的肾保护作用可能与减少糖尿病小鼠的肾脏炎症、氧化应激和凋亡有关。
