Document Detail


Development of hypertension and kidney hypertrophy in transgenic mice overexpressing ARAP1 gene in the kidney.
MedLine Citation:
PMID:  16801480     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Angiotensin II regulates blood pressure via activation of the type 1 receptor. We previously identified a novel angiotensin II type 1 receptor-associated protein and demonstrated that it promotes receptor recycling to the plasma membrane. To delineate the pathophysiological function of the ARAP1 in the kidneys, we generated transgenic mice that overexpress rat ARAP1 cDNA specifically in proximal tubules and tested the hypothesis that proximal tubule-specific overexpression of ARAP1 causes hypertension. Two lines of male transgenic mice, 650 and 670, displayed kidney-specific transgene expression. Systolic blood pressure was significantly elevated by &20 to 25 mm Hg in these lines of mice at 20 weeks of age compared with their nontransgenic litter mates. Urine volume, but not water intake, was significantly decreased in both lines compared with nontransgenic controls. The kidney/body weight ratio was significantly increased in both lines compared with their nontransgenic litter mates at 12 and 20 weeks of age. In contrast, no difference was observed in the ratio of brain, spleen, heart, and testis to body weight between male transgenic and nontransgenic animals. Inhibitions of the renin-angiotensin system completely normalized the systolic blood pressure of transgenic mice. Moreover, low salt intake prevented the development of hypertension, whereas high salt intake exacerbated the increase in blood pressure in transgenic mice. Therefore, our data show that proximal tubule-specific overexpression of ARAP1 leads to hypertension, suggesting that renal ARAP1 plays an important role in the regulation of blood pressure and renal function via activation of the intrarenal renin-angiotensin system.
Authors:
Deng-Fu Guo; Isabelle Chenier; Julie L Lavoie; John S D Chan; Pavel Hamet; Johanne Tremblay; Xiang Mei Chen; Donna H Wang; Tadashi Inagami
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-06-26
Journal Detail:
Title:  Hypertension     Volume:  48     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-08-18     Completed Date:  2006-09-18     Revised Date:  2011-08-31    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  453-9     Citation Subset:  IM    
Affiliation:
Research Centre, Centre hospitalier de l'Université de Montréal, Hôtel-Dieu, Pavillon Masson, 3850 Saint Urbain St, Montreal, Quebec, Canada H2W 1T8. guod@magellan.umontreal.ca
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / genetics,  metabolism*
Aging
Animals
Blood Pressure / drug effects
Diuresis
Dose-Response Relationship, Drug
Drug Implants
Epithelial Sodium Channel
Female
Hematocrit
Hypertension / etiology*,  physiopathology
Hypertrophy
Kidney / metabolism*,  pathology*
Male
Mice
Mice, Transgenic
RNA, Messenger / metabolism
Rats
Sodium Channels / genetics
Sodium Chloride, Dietary / administration & dosage,  pharmacology
Testosterone / administration & dosage,  pharmacology
Tissue Distribution
Grant Support
ID/Acronym/Agency:
DK67620/DK/NIDDK NIH HHS; HL-57853/HL/NHLBI NIH HHS; HL-73287/HL/NHLBI NIH HHS; HL58205/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Angptl2 protein, rat; 0/Drug Implants; 0/Epithelial Sodium Channel; 0/RNA, Messenger; 0/Sodium Channels; 0/Sodium Chloride, Dietary; 58-22-0/Testosterone
Comments/Corrections
Comment In:
Hypertension. 2006 Sep;48(3):370-1   [PMID:  16894056 ]

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