title: Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats.
abstract: OBJECTIVE
  We previously showed that the molecule interacting with Ang II type 1 receptor (AT1R), ATRAP, promotes AT1R internalization and attenuates AT1R-mediated pathological responses. In this study we examined whether the regulation of renal ATRAP expression is related to the development of salt-induced hypertension and renal injury as well as to the beneficial effects of AT1R blockade.
  
  
  RESULTS
  Dahl Iwai salt-sensitive hypertensive and Dahl Iwai salt-resistant rats were divided into six groups for the administration of vehicle or olmesartan either continuously from 3 to 16 weeks, or transiently from weaning to puberty (3-10 weeks), and fed high salt diet from 6 to 16 weeks. In Dahl Iwai salt-sensitive rats, not only continuous, but also prepubertal olmesartan treatment improved hypertension at 15 weeks. Renal ATRAP expression was suppressed in vehicle-treated Dahl Iwai salt-sensitive rats, concomitant with up-regulation of renal oxidative stress, inflammation and fibrosis-related markers such as p22phox, TGF-β, fibronectin, monocyte chemotactic protein-1 and type 1 collagen. However, prepubertal as well as continuous olmesartan treatment recovered the suppressed renal ATRAP expression and inhibited the renal activation of p22phox, TGF-β, fibronectin, MCP-1 and type 1 collagen. In Dahl Iwai salt-resistant rats, such suppression of renal ATRAP expression or induction of renal pathological responses by salt loading was not observed.
  
  
  CONCLUSIONS
  These results indicate that prepubertal transient blockade of AT1R signaling exerts a long-term therapeutic effect on salt-induced hypertension and renal injury in Dahl Iwai salt-sensitive rats, partly through a sustained enhancement of renal ATRAP expression, thereby suggesting ATRAP a novel molecular target in salt-induced hypertension and renal injury.
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Dejima
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wakui
authors.forename: Akinobu
authors.initials: A
authors.lastname: Maeda
authors.forename: Masato
authors.initials: M
authors.lastname: Ohsawa
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kanaoka
authors.forename: Sona
authors.initials: S
authors.lastname: Haku
authors.forename: Azushima
authors.initials: A
authors.lastname: Kengo
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Atsu-Ichiro
authors.initials: A
authors.lastname: Shigenaga
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.forename: Miyuki
authors.initials: M
authors.lastname: Matsuda
authors.forename: Machiko
authors.initials: M
authors.lastname: Yabana
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hirose
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Uchino
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kimura
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012083:Renin / Q000378:metabolism; D012741:Sexual Maturation; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C524087:Agtrap protein, rat; D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; C437965:olmesartan; D012083:Renin