Centro de Investigaciones Biomédicas en Red de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain.
Am J Physiol Renal Physiol. 2010 Jul;299(1):F234-42. doi: 10.1152/ajprenal.00687.2009. Epub 2010 Apr 14.
Certain determinants of ischemic resistance in the Brown Norway rat strain have been proposed, but no studies to date have focused on the role of the Wnt pathway in the ischemic resistance mechanism. We performed a comparative genomic study in Brown Norway vs. Sprague-Dawley rats. Selective manipulations of the Wnt pathway in vivo and in vitro allowed us to study whether the action of the Wnt pathway on apoptosis through the regulation of osteopontin was critical to the maintenance of inherent ischemic resistance mechanisms. The results revealed a major gene upregulation of the Wnt family in Brown Norway rats after renal ischemia-reperfusion. Manipulation of the Wnt signaling cascade by selective antibodies increased mitochondrial cytochrome c release and caspase 3 activity. The antiapoptotic role of Wnt was mediated by osteopontin, a direct Wnt target gene. Osteopontin was reduced by Wnt antibody administration in vivo, and osteopontin gene silencing in vitro significantly increased mitochondrial cytochrome c release. The overexpression of Wnt pathway genes detected in Brown Norway rats is critical in the maintenance of their inherent ischemic resistance. Activation of the Wnt signaling cascade reduces mitochondrial cytochrome c release and caspase 3 activity through the action of osteopontin.
已经提出了某些决定棕色挪威大鼠缺血抵抗的因素，但迄今为止，尚无研究关注 Wnt 途径在缺血抵抗机制中的作用。我们在棕色挪威大鼠和 Sprague-Dawley 大鼠中进行了比较基因组研究。体内和体外选择性地操纵 Wnt 途径使我们能够研究 Wnt 途径通过调节骨桥蛋白对细胞凋亡的作用是否对维持固有缺血抵抗机制至关重要。结果显示，肾缺血再灌注后，棕色挪威大鼠中 Wnt 家族的主要基因上调。通过选择性抗体操纵 Wnt 信号级联增加了线粒体细胞色素 c 释放和 caspase 3 活性。Wnt 的抗凋亡作用是通过骨桥蛋白介导的，骨桥蛋白是 Wnt 的直接靶基因。体内给予 Wnt 抗体可减少骨桥蛋白，体外沉默骨桥蛋白基因可显著增加线粒体细胞色素 c 释放。在棕色挪威大鼠中检测到的 Wnt 途径基因的过表达对维持其固有缺血抵抗至关重要。Wnt 信号级联的激活通过骨桥蛋白减少线粒体细胞色素 c 释放和 caspase 3 活性。
