Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension
Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension
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DOI：
10.1038/labinvest.2010.159
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发表时间：
2011-01-01
影响因子：
5
通讯作者：
Peters, Dorien J. M.
中科院分区：
文献类型：
--
作者：
Hassane, Sabrine;Claij, Nanna;Peters, Dorien J. M.
常染色体显性多囊肾病（ADPKD）是一种多系统疾病，以肾脏、肝脏和胰腺囊肿形成和心血管并发症为特征。这种情况是由PKD1或PKD2基因突变引起的。在Pkd1表达降低的小鼠中，可见夹层动脉瘤伴显著中膜增厚。为了研究血管平滑肌细胞（SMCs）中Pkd1选择性破坏的影响，我们在SM22启动子的控制下，用Cre删除了Pkd1基因的一个固定部分（SM22-Pkd1（del/del）小鼠）。用lacZ表达Cre报告小鼠（R26R）的X-gal染色证实了Cre的活性，定量PCR显示主动脉中Pkd1基因表达强烈降低，而Pkd2水平保持不变。组织病理学分析显示胰腺、肝脏和肾脏的囊肿形成是由于胰腺管、胆管和肾小球鲍曼囊的血管外Cre活性所致。值得注意的是，在SMCs体细胞Pkd1基因破坏或SMCs和内皮细胞（ECs） Pkd1同时破坏的小鼠中，我们没有发现任何自发的总体结构血管异常。对40周龄Pkd1（del/+）种系小鼠的主动脉进行广泛的等长肌图分析，除了苯肾上腺素对动脉收缩性的显著增加外，没有发现对KCl、乙酰胆碱、苯肾上腺素或血清素的反应有差异。然而，SM22-Pkd1（del/del）小鼠在血管紧张素ii诱导的高血压中表现出明显的心率降低。目前的研究结果进一步在体内证明，SM22-Pkd1（del/del）小鼠对高血压的适应发生了改变。实验室调查（2011）91,24-32；doi: 10.1038 / labinvest.2010.159;2010年9月20日在线发布
Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by renal, hepatic and pancreatic cyst formation and cardiovascular complications. The condition is caused by mutations in the PKD1 or PKD2 gene. In mice with reduced expression of Pkd1, dissecting aneurysms with prominent media thickening have been seen. To study the effect of selective disruption of Pkd1 in vascular smooth muscle cells (SMCs), we have generated mice in which a floxed part of the Pkd1 gene was deleted by Cre under the control of the SM22 promotor (SM22-Pkd1(del/del) mice). Cre activity was confirmed by X-gal staining using lacZ expressing Cre reporter mice (R26R), and quantitative PCR indicated that in the aorta Pkd1 gene expression was strongly reduced, whereas Pkd2 levels remained unaltered. Histopathological analysis revealed cyst formation in pancreas, liver and kidneys as the result of extravascular Cre activity in pancreatic ducts, bile ducts and in the glomerular Bowman's capsule. Remarkably, we did not find any spontaneous gross structural blood vessel abnormalities in mice with somatic Pkd1 gene disruption in SMCs or simultaneous disruption of Pkd1 in SMCs and endothelial cells (ECs). Extensive isometric myographic analysis of the aorta did not reveal differences in response to KCl, acetylcholine, phenylephrin or serotonin, except for a significant increase in contractility induced by phenylephrin on arteries from 40 weeks old Pkd1(del/+) germ-line mice. However, SM22-Pkd1(del/del) mice showed significantly reduced decrease in heart rate on angiotensin II-induced hypertension. The present findings further demonstrate in vivo, that adaptation to hypertension is altered in SM22-Pkd1(del/del) mice. Laboratory Investigation (2011) 91, 24-32; doi:10.1038/labinvest.2010.159; published online 20 September 2010