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学科主题: 基础医学
题名:
A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic
作者: Li, Fei1,2; Lei, Tianluo1,2; Zhu, Juanjuan1,2; Wang, Weiling1,2; Sun, Yi1,2; Chen, Jihui1,2; Dong, Zixun1,2; Zhou, Hong1,2; Yang, Baoxue1,2
关键词: diuretics ; electrolytes ; physiology ; renal ; urea ; water-electrolyte balance
刊名: KIDNEY INTERNATIONAL
发表日期: 2013-06-01
DOI: 10.1038/ki.2013.62
卷: 83, 期:6, 页:1076-1086
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Urology & Nephrology
研究领域[WOS]: Urology & Nephrology
关键词[WOS]: UT-B ; MICE LACKING ; SYSTOLIC HYPERTENSION ; CARDIOVASCULAR EVENTS ; CONCENTRATING ABILITY ; ELDERLY PROGRAM ; COLLECTING DUCT ; KNOCKOUT MICE ; MDCK CELLS ; ERYTHROCYTES
英文摘要:

Urea transporters (UTs) are a family of membrane channel proteins that are specifically permeable to urea and play an important role in intrarenal urea recycling and in urine concentration. Using an erythrocyte osmotic lysis assay, we screened a small-molecule library for inhibitors of UT-facilitated urea transport. A novel class of thienoquinolin UT-B inhibitors were identified, of which PU-14 had potent inhibition activity on human, rabbit, rat, and mouse UT-B. The half-maximal inhibitory concentration of PU-14 on rat UT-B-mediated urea transport was similar to 0.8 mu mol/l, and it did not affect urea transport in mouse erythrocytes lacking UT-B but inhibited UT-A-type urea transporters, with 36% inhibition at 4 mu mol/l. PU-14 showed no significant cellular toxicity at concentrations up to its solubility limit of 80 mu mol/l. Subcutaneous delivery of PU-14 (at 12.5, 50, and 100mg/ kg) to rats caused an increase of urine output and a decrease of the urine urea concentration and subsequent osmolality without electrolyte disturbances and liver or renal damages. This suggests that PU-14 has a diuretic effect by urea-selective diuresis. Thus, PU-14 or its analogs might be developed as a new diuretic to increase renal fluid clearance in diseases associated with water retention without causing electrolyte imbalance. PU-14 may establish ′chemical knockout′ animal models to study the physiological functions of UTs.

语种: 英语
所属项目编号: 30870921 ; 31200869 ; 81261160507 ; 81170632 ; 2009ZX09301-010-30 ; 20100001110047 ; 2012DFA11070 ; 7102105
项目资助者: National Natural Science Foundation of China ; Drug Discovery Program ; Research Fund for the Doctoral Program of Higher Education ; Program of Introducing Talents of Discipline to Universities ; International Science &amp ; Technology Cooperation Program of China ; Beijing Natural Science Foundation grant
WOS记录号: WOS:000319740300016
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59540
Appears in Collections:基础医学院_药理学系_期刊论文

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作者单位: 1.Peking Univ, Dept Pharmacol, Sch Basic Med Sci, Beijing 100191, Peoples R China
2.State Key Lab Nat & Biomimet Drugs, Beijing, Peoples R China

Recommended Citation:
Li, Fei,Lei, Tianluo,Zhu, Juanjuan,et al. A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic[J]. KIDNEY INTERNATIONAL,2013,83(6):1076-1086.
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