The investigation of the mechanisms and therapy of the abnormality in antidiuretic hormone action in patients with chronic renal failure

我们研究了V1a基因敲除小鼠的肾功能和异常，发现尿浓缩能力没有异常。V1a受体基因敲除小鼠的血管加压素依赖cAMP的产生也与对照小鼠没有什么不同。现在，我们正在研究V1a受体转基因小鼠。接下来，我们研究了代谢性酸中毒大鼠尿水通道蛋白-2(AQP2)的排泄情况。代谢性酸中毒大鼠尿AQP2排泄量明显减少，但外髓集合管AQP2mRNA和蛋白表达增加。这些数据提示代谢性酸中毒时AQP2从细胞内囊泡到顶膜的转运存在异常。我们在缺钾大鼠身上观察到了同样的趋势。由于细胞内酸中毒已知发生在代谢性酸中毒和钾耗竭，细胞内酸中毒可能在减少AQP2在集合管中的运输起关键作用。我们现在正在与丹麦奥胡斯大学的尼尔森博士和美国国立卫生研究院的克努珀博士合作。

We investigated renal function and abnormality in V1a-knockout mice and found that there is no abnormality in urine concentrating ability. Vasopressin-dependent camp generation in V1a receptor-knockout mice was also not different from control mice. Now, we are investigating V1a receptor transgenic mice.We next investigated urinary excretion of aquaporin-2(AQP2) in rats with metabolic acidosis. Although urinary AQP2 excretion was largely decreased, AQP2 mRNA and protein in outer medullary collecting ducts were increased in rats with metabolic acidosis. These data suggest the presence of abnormality in trafficking of AQP2 from intracellular vesicle to the apical membrane in metabolic acidosis. We observed same tendency in rats with potassium depletion. Since intracellular acidosis is known to occur in metabolic acidosis and potassium depletion, intracellular acidosis may have a key role for the decreased trafficking of AQP2 in the collecting ducts. We are now collaborating with Dr, Nielsen in Aarhus University in Denmark and Dr.knepper in National Institutes of health in USA.