IR@PKUHSC  > 北京大学基础医学院  > 药理学系
学科主题基础医学
Aquaporin-1 Translocation and Degradation Mediates the Water Transportation Mechanism of Acetazolamide
Zhang, Jianzhao1,2; An, Yu1,2; Gao, Junwei1; Han, Jing1,2; Pan, Xueyang1,2; Pan, Yan1,2; Tie, Lu1,2; Li, Xuejun1,2
刊名PLOS ONE
2012-09-21
DOI10.1371/journal.pone.0045976
7期:9
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]MEDULLARY COLLECTING DUCT ; DOWN-REGULATION ; CONCENTRATING ABILITY ; CHANNEL AQUAPORIN-2 ; RAT CHOLANGIOCYTES ; MAPK PATHWAYS ; EXPRESSION ; PERMEABILITY ; CELLS ; TRAFFICKING
英文摘要

Background: Diuretic agents are widely used on the treatment of water retention related diseases, among which acetazolamide (AZA) acts originally as a carbonic anhydrase (CA) inhibitor. Aquaporin-1 (AQP1) being located in renal proximal tubules is required for urine concentration. Previously our lab has reported AZA putatively modulated AQP1. Aim of this study is to testify our hypothesis that regulating AQP1 may mediate diuretic effect of AZA.

Methodology/Principal Findings: For in vivo study, we utilized Sprague Dawley rats, as well as AQP1 knock-out (AQP1(-/-)) mice to examine urine volume, and human kidney-2 (HK-2) cell line was used for in vitro mechanism study. In our present study we found that AZA decreased CAs activity initially but the activity gradually recovered. Contrarily, diuretic effect was consistently significant. AQP1 protein expression was significantly decreased on day 7 and 14. By utilizing AQP1(-/-) mice, we found diuretic effect of AZA was cancelled on day 14, while urine volume continuously increased in wild-type mice. Surface plasmon resonance (SPR) results indicated AQP1 was physiologically bound by myosin heavy chain (MHC), immunoprecipitation and immunofluorescence results confirmed this protein interaction. In vitro study results proved AZA facilitated AQP1 translocation onto cell membrane by promoting interaction with MHC, dependent on ERK/ myosin light chain kinase (MLCK) pathway activation. MHC inhibitor BDM and ERK inhibitor U0126 both abolished above effect of AZA. Eventually AZA induced AQP1 ubiquitination, while proteasome inhibitor MG132 reversed AZA′s down-regulating effect upon AQP1.

Conclusions/Significance: Our results identified AZA exerted diuretic effect through an innovative mechanism by regulating AQP1 and verified its inhibitory mechanism was via promoting MHC-dependent translocation onto cell membrane and then ubiquitin mediated degradation, implicating a novel mechanism and target for diuretic agent discovering.

语种英语
WOS记录号WOS:000309392800127
项目编号81020108031 ; 30572202 ; 30973558 ; 30772571 ; 30901815 ; 30901803 ; 2009ZX09103-144 ; B07001
资助机构National Natural Science Foundation of China ; Ministry of Science and Technology in China ; Ministry of Education of China
引用统计
被引频次:12[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/57858
专题北京大学基础医学院_药理学系
北京大学医学部管理机构_医学部
北京大学基础医学院
作者单位1.Peking Univ, Inst Syst Biomed, Beijing 100871, Peoples R China
2.Peking Univ, Sch Basic Med Sci, Dept Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing 100871, Peoples R China
推荐引用方式
GB/T 7714
Zhang, Jianzhao,An, Yu,Gao, Junwei,et al. Aquaporin-1 Translocation and Degradation Mediates the Water Transportation Mechanism of Acetazolamide[J]. PLOS ONE,2012,7(9).
APA Zhang, Jianzhao.,An, Yu.,Gao, Junwei.,Han, Jing.,Pan, Xueyang.,...&Li, Xuejun.(2012).Aquaporin-1 Translocation and Degradation Mediates the Water Transportation Mechanism of Acetazolamide.PLOS ONE,7(9).
MLA Zhang, Jianzhao,et al."Aquaporin-1 Translocation and Degradation Mediates the Water Transportation Mechanism of Acetazolamide".PLOS ONE 7.9(2012).
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