Upregulation of osteopontin expression in renal cortex of streptozotocin-induced diabetic rats is mediated by bradykinin
Upregulation of osteopontin expression in renal cortex of streptozotocin-induced diabetic rats is mediated by bradykinin
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DOI：
10.2337/diabetes.47.9.1512
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发表时间：
1998-09-01
期刊：
影响因子：
7.7
通讯作者：
Unger, T
中科院分区：
文献类型：
--
作者：
Fischer, JW;Tschöpe, C;Unger, T
采用链脲佐菌素（STZ）诱导的Wistar大鼠糖尿病模型，研究骨桥蛋白在糖尿病肾病发生发展过程中的表达。在12周的实验期间，通过血清葡萄糖水平超过16 mmol/l来证实糖尿病。在此期间，发生了糖尿病肾病，其特征为肾小球滤过率降低（对照组为2.7 +/- 0.3 ml/min，糖尿病大鼠为1.7 +/- 0.1 ml/min）和蛋白尿（对照组为8.3 +/- 1.7 mg/24 h，糖尿病大鼠为22.0 +/- 4 mg/24 h）。北方印迹分析显示肾皮质骨桥蛋白表达的时间依赖性上调，2周后达到对照水平的138 +/- 6%，12周后达到290 +/- 30%（平均值+/- SE，n = 6-9）。免疫组化显示骨桥蛋白表达增加的部位位于肾皮质的肾小管上皮细胞。在12周的实验期间，用雷米普利（3 mg/kg）对动物进行慢性治疗，导致糖尿病动物骨桥蛋白mRNA表达进一步增加，达到对照组的570 +/- 73%（平均值+/- SE，n = 6）。骨桥蛋白水平的增加与单核细胞/巨噬细胞的积聚无关，单核细胞/巨噬细胞的积聚由细胞类型特异性单克隆抗体艾德-1鉴定。应用缓激肽B-2受体拮抗剂艾替班特（0.5 mg/kg）可消除雷米普利预处理大鼠骨桥蛋白表达增加。此外，在Sn注射后未接受任何治疗的糖尿病大鼠中骨桥蛋白表达的增加也可以通过在实验期的最后2周给予艾替班特来降低。这些数据表明，一个强大的缓激肽B-2受体介导的上调骨桥蛋白发生在大鼠实验性糖尿病肾病的发病机制。
The model of streptozotocin (STZ)-induced diabetes in Wistar rats was used to study the expression of osteopontin during development of diabetic nephropathy. Diabetes was confirmed by serum glucose levels exceeding 16 mmol/l during the experimental period of 12 weeks. During this period of time, diabetic nephropathy developed, as characterized by a reduced glomerular filtration rate (2.7 +/- 0.3 ml/min in controls vs. 1.7 +/- 0.1 ml/min in diabetic rats) and proteinuria (8.3 +/- 1.7 mg/24 h in controls vs. 22.0 +/- 4 mg/24 h in diabetic rats). Northern blot analysis revealed a time-dependent upregulation of renal cortical osteopontin expression reaching 138 +/- 6% of control levels after 2 weeks and 290 +/- 30% (mean +/- SE, n = 6-9) after 12 weeks. By immunostaining, the increased osteopontin expression could be located to the tubular epithelium of the renal cortex. Chronic treatment of animals with ramipril (3 mg/kg) during the 12-week experimental period led to a further increase in osteopontin mRNA expression in diabetic animals, amounting to 570 +/- 73% (mean +/- SE, n = 6) of controls. Increased levels of osteopontin were not associated with accumulation of monocyte/macrophages that were identified by the cell type specific monoclonal antibody ED-1. The increased osteopontin expression in ramipril-pretreated rats was abolished by application of the bradykinin B-2-receptor antagonist, icatibant (0.5 mg/kg). In addition, increased osteopontin expression in diabetic rats, which did not receive any treatment after Sn injection, could as well be reduced by icatibant given for the final 2 weeks of the experimental period. These data suggest that a strong bradykinin B-2-receptor-mediated upregulation of osteopontin occurs during the pathogenesis of experimental diabetic nephropathy in rats.