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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-01870111/
• 关键词: Isolated nephron; PAN nephrosisis; Glomerular epithelium; Angiotensin II; Antidiuretic hormone; Cytosolic free calcium; Endothelin; Lipid peroxidation; 脂質過酸化; バゾプレシン; 昇汞; ブラディキニン; Cキナ-ゼ; マイクロパンクチャ-; 実験ネフロ-ゼ; Puromycin aminonucleoside; 活性酸素

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。肾单位异质性支持筛选系统用于评价肾脏药物作用的特征。所获得的结果包括：肾单位能量代谢、嘌呤代谢酶的定位、cAMP对肾小球内超氧化物生成的抑制作用、血管紧张素对近端小管早期胞浆钙瞬变的双相增强作用、近端小管上一种新的加压素受体、甘氨酸亲和素转移酶在肾脏内的定位、大鼠肾节段的脂质过氧化以及大鼠肾内蛋白质的处理。肾作用药物的筛选系统：产生PGE2的肾内部位高度异质性，环状利尿剂选择性地增加粗大的升肢中PGE2的聚集，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短环，但不作用于离子环，这可通过测定三磷酸腺苷周转率…得出结论更多地使用孤立的肾单位节段。抗肾药可增强腺苷对肾小球的作用，这与其抑制自由基形成的作用密切相关。通过对肾内脂质过氧化反应的评估，可以确定早期近端小管是糖尿病肾病早期的一个致病部位。蛙尿膀胱可用于鉴定肾脏药物作用的细胞内坏死，特别是钠离子转运与蛋白激酶偶联的作用。评价肾毒性的筛选系统：细胞内ATP周转和激动剂诱导的胞内游离钙瞬变是沿着肾单位定量肾毒性的敏感和有用的决定因素。肾脏糖异生和氨化等代谢功能可以在组织学改变之前发现肾毒性的早期迹象。上述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，而且为更好地理解这些药物的作用机制带来了值得注意的信息。较少

项目成果

Jung, K. Y. and Endou, H.: "Nephrotoxicity assessment by measuring cellular ATP content II. Intra-nephron site of ochrratoxin A nephrotoxicity." Toxicol. Appl. Pharmacol.100. 383-390 (1989)

Jung, K. Y. 和 Endou, H.：“通过测量细胞 ATP 含量进行肾毒性评估 II。赭曲霉毒素 A 肾毒性的肾单位内位点。”

Miyanoshita, A., Takahashi, T. and Endou, H.: "Inhibitory effect of cyclic AMP on phorbol estere stimulated production of reactive oxygen metabolites in rat glomeruli." Biochem. Biophys. Res. Commun.165(1). 519-525 (1989)

Miyanoshita, A.、Takahashi, T. 和 Endou, H.：“环 AMP 对佛波酯的抑制作用刺激了大鼠肾小球中活性氧代谢物的产生。”

Miyanoshita, A., Terada, M. and Endou, H.: "Furosemide directly stimulates prostaglandin E_2 production in the thick ascending limbof Henle's loop" J. Pharmacol. Exp. Ther.251(3). 1155-1159 (1989)

Miyanoshita, A.、Terada, M. 和 Endou, H.：“呋塞米直接刺激亨利氏袢厚升肢中前列腺素 E_2 的产生”J. Pharmacol。

Satoh, T. and Endou, H.: "Inhibitory effect of phorbol ester on sodium transport in frog urinary bladder." Am. J. Physiol.259. F425-F431 (1990)

Satoh, T. 和 Endou, H.：“佛波酯对青蛙膀胱钠转运的抑制作用。”

Endou,H.et al.: "Adenosine 2 receptor distribution along the rat nephron and its role in generation of oxygen metabolites in glomeruli" The frontiers of Nephrology. (1990)

Endou, H. 等人：“腺苷 2 受体沿大鼠肾单位的分布及其在肾小球中氧代谢物生成中的作用”肾脏病学前沿。