Inhibition of the janus (JAK)/signal transducers of activated transcription (STAT) pathway prevents the development of angiotensin II‐induced hypertension

Angiotensin II (ANG II) is a major physiologic and pathophysiologic controller of arterial pressure, but the molecular mechanisms underlying that effect are not completely understood. ANG II activates the JAK/STAT pathway in vitro and in vivo in models of type I diabetes but whether this activation occurs in hypertension and is required for ANG II-mediated increases in blood pressure are unknown. Therefore we tested the hypothesis that inhibition of the JAK/STAT pathway would attenuate ANG II-induced hypertension. We utilized male Sprague-Dawley rats, chronically catheterized for 24 hr/day iv infusion and mean arterial pressure (MAP) measurements. All rats were maintained on a high-salt intake (~12 mEq/day), and after control measurements ANG II (10 ng/kg/min, iv) was infused with or without the JAK2 inhibitor AG490 (10 ng/kg/min, iv). After 5 days of ANG II infusion the rats receiving AG490 had significantly lower MAP than the ANG II alone rats (106 + 6.1 vs 144 + 4.9 mm Hg, respectively). When AG490 was stopped during continued ANG II infusion, MAP rose within 1 day to match MAP in the ANG II alone group (158+ 2.1 vs 168 + 6.9, respectively). Western blot analysis revealed that JAK2 activation was significantly inhibited in the ANG II/AG490-treated rats. From these data we conclude that activation of the JAK/STAT pathway is critical for the development of ANG II-induced hypertension. (AHA SDG ABB, HL-56259, HL-74167 MWB).