IR@PKUHSC  > 北京大学基础医学院  > 药理学系
学科主题基础医学
Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters
Ren, Huiwen1; Wang, Yanhua2,3; Xing, Yongning1; Ran, Jianhua4; Liu, Ming1; Lei, Tianluo1; Zhou, Hong1; Li, Runtao1; Sands, Jeff M.2,3; Yang, Baoxue1,5
关键词diuretics urine concentrating mechanism drug discovery drug target vasopressin
刊名AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
2014-12-15
DOI10.1152/ajprenal.00421.2014
307期:12页:F1363-F1372
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Physiology ; Urology & Nephrology
资助者National Natural Science Foundation of China ; Research Fund for the Doctoral Program of Higher Education ; 111 Project ; International Science &amp ; Technology Cooperation Program of China ; National Institute of Diabetes and Digestive and Kidney Diseases ; National Natural Science Foundation of China ; Research Fund for the Doctoral Program of Higher Education ; 111 Project ; International Science &amp ; Technology Cooperation Program of China ; National Institute of Diabetes and Digestive and Kidney Diseases
研究领域[WOS]Physiology ; Urology & Nephrology
关键词[WOS]NEPHROGENIC DIABETES-INSIPIDUS ; URINARY CONCENTRATING DEFECT ; MEDULLARY COLLECTING DUCTS ; MEMBRANE ACCUMULATION ; DIURETIC THERAPY ; INCREASES PHOSPHORYLATION ; ANTIMICROBIAL ACTIVITY ; PLASMA-MEMBRANE ; WATER CHANNELS ; MDCK CELLS
英文摘要

Urea transporters (UT) play an important role in the urine concentration mechanism by mediating intrarenal urea recycling, suggesting that UT inhibitors could have therapeutic use as a novel class of diuretic. Recently, we found a thienoquinolin UT inhibitor, PU-14, that exhibited diuretic activity. The purpose of this study was to identify more potent UT inhibitors that strongly inhibit UT-A isoforms in the inner medullary collecting duct (IMCD). Efficient thienoquinolin UT inhibitors were identified by structure-activity relationship analysis. Urea transport inhibition activity was assayed in perfused rat terminal IMCDs. Diuretic activity of the compound was determined in rats and mice using metabolic cages. The results show that the compound PU-48 exhibited potent UT-A inhibition activity. The inhibition was 69.5% with an IC50 of 0.32 mu M. PU-48 significantly inhibited urea transport in perfused rat terminal IMCDs. PU-48 caused significant diuresis in UT-B null mice, which indicates that UT-A is the target of PU-48. The diuresis caused by PU-48 did not change blood Na+, K+, or Cl- levels or nonurea solute excretion in rats and mice. No toxicity was detected in cells or animals treated with PU-48. The results indicate that thienoquinolin UT inhibitors induce a diuresis by inhibiting UT-A in the IMCD. This suggests that they may have the potential to be developed as a novel class of diuretics with fewer side effects than classical diuretics.

语种英语
所属项目编号31200869 ; 81261160507 ; 81330074 ; 81170632 ; 20100001110047 ; 2012DFA11070 ; R01-DK-89828 ; R01-DK-41707
资助者National Natural Science Foundation of China ; Research Fund for the Doctoral Program of Higher Education ; 111 Project ; International Science &amp ; Technology Cooperation Program of China ; National Institute of Diabetes and Digestive and Kidney Diseases ; National Natural Science Foundation of China ; Research Fund for the Doctoral Program of Higher Education ; 111 Project ; International Science &amp ; Technology Cooperation Program of China ; National Institute of Diabetes and Digestive and Kidney Diseases
WOS记录号WOS:000346480900007
Citation statistics
Cited Times:5[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/66269
Collection北京大学基础医学院_药理学系
作者单位1.Peking Univ, Sch Basic Med Sci, Dept Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Emory Univ, Sch Med, Dept Med, Div Renal, Atlanta, GA 30322 USA
3.Emory Univ, Sch Med, Dept Physiol, Atlanta, GA 30322 USA
4.Chongqing Med Univ, Basic Med Coll, Neurosci Res Ctr, Dept Anat, Chongqing, Peoples R China
5.Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China
Recommended Citation
GB/T 7714
Ren, Huiwen,Wang, Yanhua,Xing, Yongning,et al. Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters[J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY,2014,307(12):F1363-F1372.
APA Ren, Huiwen.,Wang, Yanhua.,Xing, Yongning.,Ran, Jianhua.,Liu, Ming.,...&Yang, Baoxue.(2014).Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters.AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY,307(12),F1363-F1372.
MLA Ren, Huiwen,et al."Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters".AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 307.12(2014):F1363-F1372.
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