Establishment of screening systems for evaluating drug actions in the kidney

1 .支持筛选系统评价肾脏药物作用的肾单位异质性特征。研究结果包括肾元能量代谢、嘌呤代谢酶的定位、CAMP对肾小球超氧化物生成的抑制作用、血管紧张素对早期近端小管胞质钙瞬态的双相增加作用、近端小管中一种新的加压素受体、肾内甘氨酸氨基转移酶的定位、大鼠肾元段的脂质过氧化和大鼠肾内蛋白质处理。评价肾作用药物的筛选系统。肾内产生PGE2的部位是高度不均匀的，袢利尿剂选择性地增加了PGE2在粗升肢中的含量，提示PGE2可能是导致利尿的生理介质。速尿也作用于下行细肢的短环，但不作用于离子环，这可以通过测定ATP的周转率得出结论。抗肾病药物可增强腺苷对肾小球的作用，其作用与抑制自由基形成密切相关。肾内脂质过氧化的估计使得鉴别早期近端小管作为糖尿病肾病早期的致病部位成为可能。蛙膀胱可用于鉴别肾脏药物作用的细胞内机制，特别是钠离子转运与蛋白激酶C.3的作用。评估肾毒性的筛选系统。细胞内ATP转换和激动剂诱导的胞质游离钙瞬变是量化肾单位肾毒性的敏感和有用的决定因素。代谢功能如肾糖异生和氨生成可用于发现肾毒性的早期迹象之前的组织学改变。以上总结的结果不仅可以对肾作用药物和肾毒性药物进行分类，而且为更好地了解这些药物的作用机制提供了重要的信息。少

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