Osmotic response element-binding protein (OREBP) is an essential regulator of the urine concentrating mechanism
Osmotic response element-binding protein (OREBP) is an essential regulator of the urine concentrating mechanism
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DOI：
10.1074/jbc.m407224200
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发表时间：
2004-11-12
影响因子：
4.8
通讯作者：
Chung, SSM
中科院分区：
文献类型：
--
作者：
Lam, AKM;Ko, BCB;Chung, SSM
OREBP（渗透压反应元件结合蛋白），也称为TonEBP或NFAT 5，被认为可以诱导增加有机渗透压物质积累的基因表达，以保护细胞免受高渗环境的影响。为了研究缺乏OREBP活性的后果，产生了特异性地在肾集合小管的上皮细胞中过表达OREBPdn（OREBP的显性阴性形式）的转基因（Tg）小鼠。这些小鼠的尿液浓缩机制受损，很可能是由于水通道蛋白AQP 2和尿素转运蛋白UT-A1和UT-A2 mRNA的表达减少。当剥夺水或后加压素类似物的管理，尿渗透压的Tg小鼠显着增加，但不相同的程度，野生型小鼠。AQP 2和UT-A1的表达，而不是UT-A2的mRNA，增加到与野生型小鼠在水剥夺状态下相同的水平，表明加压素调节机制不受OREBPdn的影响。这些数据表明，除了加压素，OREBP是尿液浓缩机制的另一个重要调节剂。此外，OREBPdn Tg小鼠在断奶后不久发生进行性肾积水，证实了体外实验所涉及的OREBP的肾脏保护功能。
OREBP (osmotic response element-binding protein), also called TonEBP or NFAT5, is thought to induce the expression of genes that increase the accumulation of organic osmolytes to protect cells against a hypertonic environment. To investigate the consequences of lacking OREBP activity, transgenic (Tg) mice that overexpress OREBPdn (dominant negative form of OREBP) specifically in the epithelial cells of the renal collecting tubules were generated. These mice showed impairment in their urine concentrating mechanism, most likely due to reduced expression of the aquaporin AQP2 and the urea transporter UT-A1 and UT-A2 mRNAs. When deprived of water or after the administration of a vasopressin analogue, urine osmolality of the Tg mice was significantly increased but not to the same extent as that of the wild type mice. The expression of AQP2 and UT-A1, but not UT-A2 mRNAs, was increased to the same level as that of the wild type mice in the water deprivation state, indicating that the vasopressin regulatory mechanism was not affected by OREBPdn. These data indicate that in addition to vasopressin, OREBP is another essential regulator of the urine concentrating mechanism. Furthermore, the OREBPdn Tg mice developed progressive hydronephrosis soon after weaning, confirming the osmoprotective function of OREBP implicated by the in vitro experiments.