title: Angiotensin II utilizes Janus kinase 2 in hypertension, but not in the physiological control of blood pressure, during low-salt intake.
abstract: Janus kinase (JAK) 2 is activated by ANG II in vitro and in vivo, and chronic blockade of JAK2 by the JAK2 inhibitor AG-490 has been shown recently to attenuate ANG II hypertension in mice. In this study, AG-490 was infused intravenously in chronically instrumented rats to determine if the blunted hypertension was linked to attenuation of the renal actions of ANG II. In male Sprague-Dawley rats, after a control period, ANG II at 10 ng·kg(-1)·min(-1) was infused intravenously with or without AG-490 at 10 ng·kg(-1)·min(-1) iv for 11 days. ANG II infusion (18 h/day) increased mean arterial pressure from 91 ± 3 to 168 ± 7 mmHg by day 11. That response was attenuated significantly in the ANG II + AG-490 group, with mean arterial pressure increasing only from 92 ± 5 to 127 ± 3 mmHg. ANG II infusion markedly decreased urinary sodium excretion, caused a rapid and sustained decrease in glomerular filtration rate to ∼60% of control, and increased renal JAK2 phosphorylation; all these responses were blocked by AG-490. However, chronic AG-490 treatment had no effect on the ability of a separate group of normal rats to maintain normal blood pressure when they were switched rapidly to a low-sodium diet, whereas blood pressure fell dramatically in losartan-treated rats on a low-sodium diet. These data suggest that activation of the JAK/STAT pathway is critical for the development of ANG II-induced hypertension by mediating its effects on renal sodium excretory capability, but the physiological control of blood pressure by ANG II with a low-salt diet does not require JAK2 activation.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta, Georgia, USA. banesber@oakland.edu
authors.forename: Amy K L
authors.initials: AK
authors.lastname: Banes-Berceli
authors.forename: Hind
authors.initials: H
authors.lastname: Al-Azawi
authors.forename: Daniel
authors.initials: D
authors.lastname: Proctor
authors.forename: Harvey
authors.initials: H
authors.lastname: Qu
authors.forename: Dominic
authors.initials: D
authors.lastname: Femminineo
authors.forename: Crystal
authors.initials: C
authors.lastname: Hill-Pyror
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Michael W
authors.initials: MW
authors.lastname: Brands
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D004039:Diet, Sodium-Restricted; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007262:Infusions, Intravenous; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020032:Tyrphostins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000804:Angiotensin II; C507927:Jak2 protein, rat; D053614:Janus Kinase 2