Fetal Kidney Tissue Transplantation And Bmp-7-induced Ne

胎儿肾组织移植和Bmp-7诱导的Ne

• 批准号: 6680428
• 负责人: Yun Wang
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6680428
• 关键词: bone morphogenetic proteins; cerebral artery; cerebral cortex; cerebral ischemia /hypoxia; cysteine endopeptidases; embryo /fetus tissue transplantation; enzyme activity; infarct; kidney transplantation; laboratory rat; neuroprotectants; nonhuman therapy evaluation; reperfusion; stroke; stroke therapy

Both bone morphogenetic protein-7 (BMP-7) and glial cell line derived neurotrophic factor (GDNF) reduce ischemia-induced cerebral injury in rats. Intracerebral transplantation of fetal kidney tissue, in which BMP-7 and GDNF play important roles during development, reduced ischemic injury in cerebral cortex. In this study, we tested the hypothesis that BMP-7 is involved in this neuroprotective response. Fetal kidney tissues were cut into small pieces and transplanted into cortical areas adjacent to the right middle cerebral artery (MCA) distribution in anesthetized adult Sprague-Dawley rats. In situ hybridization study indicates that these fetal kidney transplants contained high levels of BMP-7 mRNA 3 days after grafting. Some animals were grafted with fetal kidney tissues after intraventricular administration (ICV) of the BMP-7 antagonist noggin (1 mg) or after ICV vehicle. The right MCA was later transiently ligated for 60 min. Animals receiving fetal kidney tissue transplantation developed significantly less body asymmetry, as compared to stroke animals that received no transplantation, or that received fetal kidney grafts and noggin pretreatment. Animals were later sacrificed and brains were removed for triphenyltetrazolium chloride staining. We found that transplantation of fetal kidney tissue reduced the volume of infarction in the cerebral cortex. Noggin pretreatment reduced the protection induced by fetal kidney grafting. A subgroup of animals were sacrificed 8 hours after ischemia for assay of caspase-3 enzymatic activity. Fetal kidney grafts significantly reduced ischemia-induced caspase-3 activity. This reduction could also be antagonized by noggin. In conclusion, our data suggest that fetal kidney transplantation reduces ischemia/reperfusion -induced cortical infarction and behavioral deficits in adult rats, which are, at least partially, mediated through the effect of BMP-7 in the transplants.

骨形态发生蛋白-7 （BMP-7）和神经胶质细胞系源性神经营养因子（GDNF）均能减轻大鼠缺血性脑损伤。胎儿肾组织脑内移植可减轻大脑皮质缺血性损伤，其中BMP-7和GDNF在发育过程中发挥重要作用。在这项研究中，我们验证了BMP-7参与这种神经保护反应的假设。将胎儿肾组织切成小块，移植到麻醉的成年sd大鼠右侧大脑中动脉（MCA）附近的皮质区。原位杂交研究表明，这些胎儿肾移植在移植后3天含有高水平的BMP-7 mRNA。一些动物在脑室内给药（ICV） BMP-7拮抗剂noggin （1mg）或ICV载药后移植胎儿肾组织。随后短暂结扎右MCA 60分钟。与未接受移植或接受胎儿肾移植和脑蛋白预处理的中风动物相比，接受胎儿肾组织移植的动物明显减少了身体不对称。随后处死动物，取脑进行三苯基四唑氯染色。我们发现胎儿肾组织移植减少了大脑皮层梗死的体积。头蛋白预处理降低胎儿肾移植的保护作用。亚组动物缺血8小时后处死，测定caspase-3酶活性。胎儿肾移植可显著降低缺血诱导的caspase-3活性。这种减少也可以被noggin拮抗。总之，我们的数据表明，胎儿肾移植减少了成年大鼠缺血/再灌注诱导的皮质梗死和行为缺陷，这至少部分是通过移植中BMP-7的作用介导的。