Establishment of screening systems for evaluating drug actions in the kidney

建立评估肾脏药物作用的筛选系统

基本信息

批准号：
01870111
负责人：
ENDOU Hitoshi
金额：
$ 7.87万
依托单位：
Faculty of Medicine, University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1991
项目状态：
已结题

项目摘要

l. Characteristies of nephron heterogeneity supporting screening systems tor the evaluation of renal drug actions.The results obtained include nephron energy metabolism, localization of purine-metabolizing enzymes, inhibitory effect of CAMP on superoxide generation in gloseruli, biphasic increasing effect of angiotensin I]on cytosolic calcium transient in early proximal tubule, a novel vasopressin receptor in the proximal tubule, localization of glycine avidinotransferase within the kidney, lipid peroxidation in rat nephron segments, and intrarenal handling of proteins in rats.2. Screening systems for the evaluation of kidney-acting drugs.Intrarenal sites of PGE2 production are highly heterogeneous, and loop diuretics increase PGE2 accuiu'ation selectively in the thick ascending limb suggesting PGE2 as a possible physiological mediator to cause diuresis. Furosemide also acts on short loop of descending thin limb, but not on Ions loop, that could be concluded by determining ATP turnover … More using isolated nephron seg2ents. Antinephrotic drugs potentiate adenosine action on glo2eruli which is well correlated with 'suppressive effect on free radical formation. Estimation of intranephron lipid peroxidation makes it possible to identify the early proximal tubule as a causative site of early stage in diabetic nephropathy. Frog urinary bladde can be used to identify intra cellular nechanislis of renal drug action especially on sodium ion transport coupled with protein kinase C.3. Screening systems for the evaluation of nephrotoxicity.Intracellular ATP turnover and agonist-induced cytosolic free calcium transients are sensitive and useful determinants to quantify nephrotoxicity along the nephron. Metabolic functions such as renal gluconeogenesis and ammoniagenesis can be used to find very early signs of nephrotoxicity prior to histological alterations.The above-summarized results can not only classify kidney-acting and nephrotoxic drugs, but also bring notable informations for the better understanding nechanisums of these drug actions. Less

l。 Characteristics of nephron heterogeneity supporting screening systems to the evaluation of renal drug actions.The results obtained include nephron energy metabolism, localization of pure-metabolizing enzymes, inhibitory effect of CAMP on superoxide generation in glosseruli, biphasic increasing effect of angiotensin I] on cytosolic calcium transient in early proximal tube, a novel vasopressin receptor in the近端管，肾脏中甘氨酸转移酶在肾脏中的定位，大鼠肾单位段中的脂质过氧化以及大鼠蛋白质的元素处理。2。用于评估肾脏作用药物的筛查系统。PGE2产生的心脏位点高度异质，并且在较厚的上升肢体中，循环利尿剂选择性地增加了PGE2 Accuiu'ation，这表明PGE2作为可能的物理介体可能引起利尿作用。速尿还可以作用于降细胞的短循环，而不是在离子环上，抗肾脏脂质的过氧化使得可以识别早期近端小管作为糖尿病性肾病早期阶段的病因。青蛙尿bladde可用于识别肾脏药物作用的细胞内nechanislis，尤其是在钠离子转运和蛋白激酶C.3的钠离子转运上。评估肾毒性的筛查系统。侵袭性ATP周转率和激动剂诱导的胞质游离钙瞬变是敏感且有用的确定剂，可以定量沿着肾单位的肾毒性。在组织学改变之前，可以使用诸如肾糖原发生和氨基毒素的代谢功能来找到非常早期的肾毒性迹象。上述结果不仅可以对肾脏作用和肾毒性药物进行分类，而且还可以对这些药物作用更好地理解这些药物。较少的