Terminal renal failure in mice lacking transcription factor AP-2β
Terminal renal failure in mice lacking transcription factor AP-2β
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DOI：
10.1097/01.lab.0000064703.92382.50
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发表时间：
2003-04-01
影响因子：
5
通讯作者：
Buettner, R
中科院分区：
文献类型：
--
作者：
Moser, M;Dahmen, S;Buettner, R
在基因混合的C57BU6/129S1小鼠品系中，转录因子AP-2β的失活导致围产期死亡，原因是肾上皮细胞的大量凋亡死亡(基因Dev 1997；11：19381948)。最近，我们观察到这种表型受到遗传背景的调节，因为AP-2β突变小鼠在129P2背景上回交，出生后大约2周存活，这使得对肾功能的详细分析成为可能。在这里，我们看到肾脏显示了来自所有肾小管结构(近端和远端肾小管、集合管)的不同数量的囊肿。然而，无论包囊形成的程度如何，所有的小鼠都死亡了。AP-2β突变动物的血清分析显示，肾小管分泌功能和离子平衡存在缺陷，包括严重的低钙血症、高磷血症和高尿毒症。由于激素钙调节没有受损，小鼠出现了继发性肾功能亢进，就像在终末期肾功能衰竭患者中常见的那样。我们进一步证明，集合管系统中的分子缺陷导致水保持和尿液浓度不足。综上所述，我们的研究揭示了AP-2β在肾小管功能中的基本的、非多余的作用。
Inactivation of the transcription factor AP-2beta in a genetically mixed C57BU6/129S1 mouse strain resulted in perinatal lethality as a consequence of massively enhanced apoptotic death of renal epithelial cells (Genes Dev 1997;11:19381948). Recently, we observed that the phenotype is modulated by genetic background because AP-2beta mutant mice, backcrossed onto 129P2 background, survive approximately 2 weeks after birth, allowing for a detailed analysis of kidney function. Here we show that kidneys reveal Varying amounts of cysts derived from all tubular structures (proximal and distal tubuli, collecting ducts). However, all mice died irrespective of the degree of cyst formation. Serum analysis of AP-2beta mutant animals revealed defective tubular secretory function and ion homeostasis including severe hypocalcemia, hyperphosphatemia, and hyperuremia. Because hormonal calcium regulation was not impaired, the mice developed secondary renal hyperparathyroidism as typically observed in patients with terminal renal failure. We further demonstrate that molecular defects in the collecting duct system lead to insufficient water retention and urinary concentration. In summary, our studies reveal essential, nonredundant roles of AP-2beta in renal tubular functions.