Angiotensin ii utilizes Janus kinase 2 in hypertension, but not in the physiological control of blood pressure, during low-salt intake

Amy K.L. Banes-Berceli, Hind Al-Azawi, Daniel Proctor, Harvey Qu, Dominic Femminineo, Crystal Hill-Pyror, R. Clinton Webb, Michael W. Brands

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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.

Original languageEnglish (US)
Pages (from-to)R1169-R1176
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume301
Issue number4
DOIs
Publication statusPublished - Oct 1 2011

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Keywords

  • AG-490
  • Intracellular signaling
  • Losartan
  • Mean arterial pressure
  • Sodium- deficient diet

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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