Rend cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor
Rend cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor
复制标题
DOI：
10.1158/0008-5472.can-05-3241
复制
发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Haase, VH
中科院分区：
文献类型：
--
作者：
Rankin, EB;Tomaszewski, JE;Haase, VH
von Hippel-Lindau肿瘤抑制因子pVHL的失活与遗传性和散发性肾囊肿和肾细胞癌相关，这些疾病通常被认为是由肾近端小管引起的。pVHL调节缺氧诱导因子（HIF）-α亚基的蛋白质稳定性，并且pVHL功能的丧失导致HIF稳定。HIF在VHL相关肾脏病变发展中的作用仍有待确定。为了研究pVHL失活的功能后果和HIF信号在肾上皮细胞中的作用，我们使用磷酸烯醇式丙酮酸羧激酶（PEPCK）启动子产生转基因小鼠，其中Cre重组酶在肾近端小管和肝细胞中表达。我们发现PEPCK-Cre突变体中VHL的条件性失活导致肾囊肿的发展，这与促红细胞生成素水平升高和红细胞增多症有关。HIF靶基因促红细胞生成素的表达增加仅限于肝脏，而碳酸酐酶9和maltidrug耐药基因1的表达在突变小鼠的肾皮质中上调。HIF-1 α结合伴侣-芳香烃受体核转运蛋白（Arnt）的失活抑制了肾囊肿的发展，但HIF-1 α却没有。在这里，我们提出了第一个VHL相关肾病小鼠模型，这将为进一步的遗传研究提供基础，以确定VHL相关肾囊肿发展为肾透明细胞癌所需的分子事件。
Inactivation of the von Hippel-Lindau tumor suppressor, pVHL, is associated with both hereditary and sporadic renal cysts and renal cell carcinoma, which are commonly thought to arise from the renal proximal tubule. pVHL regulates the protein stability of hypoxia-inducible factor (HIF)-alpha subunits and loss of pVHL function leads to HIF stabilization. The role of HIF in the development of VHL-associated renal lesions remains to be determined. To investigate the functional consequences of pVHL inactivation and the role of HIF signaling in renal epithelial cells, we used the phosphoenolpyruvate carboxykinase (PEPCK) promoter to generate transgenic mice in which Cre-recombinase is expressed in the renal proximal tubule and in hepatocytes. We found that conditional inactivation of VHL in PEPCK-Cre mutants resulted in renal cyst development that was associated with increased erythropoietin levels and polycythemia. Increased expression of the HIF target gene erythropoietin was limited to the liver, whereas expression of carbonic anhydrase 9 and maltidrug resistance gene 1 was up-regulated in the renal cortex of mutant mice. Inactivation of the HIF-alpha binding partner, arylhydrocarbon receptor nuclear translocator (Arnt), but not Hif-1 alpha, suppressed the development of renal cysts. Here, we present the first mouse model of VHL-associated renal disease that will provide a basis for further genetic studies to define the molecular events that are required for the progression of VHL-associated renal cysts to clear cell renal cell carcinoma.