Development of the drug which prevents the induction of acute renal failure and its clinical application

本研究旨在阐明内皮素（ET）及其受体在急性肾功能衰竭进展中的作用，并开发抑制ET作用的急性肾功能衰竭预防药物。在阐明ET在急性肾功能衰竭中的作用方面，研究取得了较好的进展。ET3几乎在肾脏的所有部位都有表达，提示其在肾脏功能中的重要作用（文献1）。集管细胞的ET1产生受到许多刺激，如高渗透压（参考文献2）。ET3刺激肾小球系膜细胞的NO合成，从而刺激cGMP的产生。这些事件证实了ET在肾脏功能调节中的重要性。基于这些发现，我们试图培养抗ET受体（主要是ETA受体）的抗体来抑制ET的作用。我们用几种不同的方法对兔子进行免疫，并获得了一些抗体。然而，这些抗体都不能抑制ET在肾功能中的作用，尽管其中一些抗体能识别受体。一般来说，获得一种良好的疏水激素受体抗体是非常困难的。我们应该进一步努力获得一种好的抗体，但也可以考虑其他方法。

In this research, we intended t o clarify the role of entothelins (ET) and their receptors in the progression of acute renal failure, and to develop the priventive drug for acute renal failure which inhibits the action of ET.The research has been performed well in respect of clarifying the role of ET in acute renal failure. ET3 is expressed in almost all parts of the kidney, suggesting its important role in kidney function (Ref.1). ET1 production in collectiong duct cells is subjects to many stimulus such as hyperosmolality (Ref.2). ET3 stimulates NO synthesis in glomerular mesangial cells which in turn stimulats cGMP production. These events establish the importance of ET in regulation of kidney functions.Based on these findings we have tried to raise antibodies against ET receptors (mainly, ETA recptor) which inhibits ET action. We immunized rabbits using several different methods, and obtained a number of antibodies. However, none of these antibodies inhibited the action of ET in kidney fuunction, although some of them recongnised the receptors. It is a general rule that obtaining a good antibody for hydrophobic hormone receptor is extremely difficult. We should try further to obtain a good antibody, but alternative approaches may be considered.