Wang Liming, Flannery Patrick J, Athirakul Krairerk, Dunn Stephen R, Kourany Wissam M, Spurney Robert F
Division of Nephrology, Department of Medicine, Duke University, Durham, NC 27710, USA.
Am J Physiol Renal Physiol. 2006 Oct;291(4):F781-9. doi: 10.1152/ajprenal.00401.2005. Epub 2006 Apr 11.
We used the mouse nephrin promoter to express a constitutively active Galphaq [Galphaq(Q>L)] transgene in mice. As previously reported, the transgene was expressed in kidney, pancreas, and brain, and the kidney phenotype was characterized by albuminuria and reduced nephron mass. Additional studies revealed a second phenotype characterized by polyuria and polydipsia. The polyuric phenotype was not caused by abnormal glucose metabolism or hypercalcemia but was accompanied by reduced urinary concentrating ability. Additional studies found that 1) water restriction was associated with an appropriate increase in serum vasopressin levels in transgenic (TG) mice; 2) the urinary concentrating defect was not corrected by administration of desamino-d-arginine vasopressin (DDAVP); and 3) papillary length was similar in TG and non-TG mice. To examine the renal response to DDAVP at the molecular level, we monitored aquaporin 2 (AQP2) and vasopressin V2 receptor (V2R) mRNA levels in mouse kidney. Consistent with the known effects of vasopressin, administration of DDAVP caused a decrease in V2R mRNA levels and an increase in AQP2 mRNA levels in both TG and non-TG animals, suggesting an appropriate renal response to DDAVP in the TG mice. To determine whether the urine concentrating abnormality was the result of primary polydipsia, water intake by TG mice was restricted to the amount ingested by non-TG animals. After 5 days, urinary concentrating ability was similar in TG mice and non-TG littermate controls. These data are consistent with the notion that expression of the Galphaq(Q>L) transgene in the brain induced primary polydipsia in the TG mice.
我们利用小鼠nephrin启动子在小鼠中表达组成型活性Gαq [Gαq(Q>L)]转基因。如先前报道，该转基因在肾脏、胰腺和大脑中表达，肾脏表型的特征为蛋白尿和肾单位数量减少。进一步研究揭示了以多尿和烦渴为特征的第二种表型。多尿表型并非由异常糖代谢或高钙血症引起，而是伴有尿浓缩能力降低。进一步研究发现：1）限水与转基因（TG）小鼠血清血管加压素水平的适当升高相关；2）给予去氨基-D-精氨酸血管加压素（DDAVP）不能纠正尿浓缩缺陷；3）TG小鼠和非TG小鼠的乳头长度相似。为了在分子水平上研究肾脏对DDAVP的反应，我们监测了小鼠肾脏中 aquaporin 2（AQP2）和血管加压素V2受体（V2R）的mRNA水平。与血管加压素的已知作用一致，给予DDAVP导致TG和非TG动物的V2R mRNA水平降低，AQP2 mRNA水平升高，提示TG小鼠对DDAVP有适当的肾脏反应。为了确定尿浓缩异常是否是原发性烦渴的结果，将TG小鼠的饮水量限制在非TG动物的摄入量。5天后，TG小鼠和非TG同窝对照小鼠的尿浓缩能力相似。这些数据与Gαq(Q>L)转基因在大脑中的表达诱导TG小鼠原发性烦渴的观点一致。
