title: Development of hypertension and kidney hypertrophy in transgenic mice overexpressing ARAP1 gene in the kidney.
abstract: 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.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
authors.forename: Deng-Fu
authors.initials: DF
authors.lastname: Guo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chenier
authors.forename: Julie L
authors.initials: JL
authors.lastname: Lavoie
authors.forename: John S D
authors.initials: JS
authors.lastname: Chan
authors.forename: Pavel
authors.initials: P
authors.lastname: Hamet
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.forename: Xiang Mei
authors.initials: XM
authors.lastname: Chen
authors.forename: Donna H
authors.initials: DH
authors.lastname: Wang
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inagami
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000375:Aging; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004231:Diuresis; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D053503:Epithelial Sodium Channels; D005260:Female; D006400:Hematocrit; D006973:Hypertension / Q000209:etiology* / Q000503:physiopathology; D006984:Hypertrophy; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015222:Sodium Channels / Q000235:genetics; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D013739:Testosterone / Q000008:administration & dosage / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; C479625:Angptl2 protein, rat; D004343:Drug Implants; D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; D015222:Sodium Channels; D017673:Sodium Chloride, Dietary; D013739:Testosterone