Interleukin 6 knockout prevents angiotensin II hypertension: role of renal vasoconstriction and janus kinase 2/signal transducer and activator of transcription 3 activation

Abstract

Chronic angiotensin II (Ang II) infusion stimulates interleukin (IL) 6 release, and we and others have shown that preventing the increase in IL-6 significantly attenuates Ang II hypertension. This study measured renal blood flow (RBF) chronically, using Transonic flow probes in wild-type (WT) and IL-6 knockout (KO) mice, to determine the role of RBF regulation in that response. Ang II infusion at 200, 800, and 3600 ng/kg per minute caused a dose-dependent decrease in RBF in WT mice, and the response at 800 ng/kg per minute was compared between WT and IL-6 KO mice. Ang II infusion increased plasma IL-6 concentration in WT mice and increased mean arterial pressure (19 h/d with telemetry) from 113±4 to 149±4 mm Hg (Δ36 mm Hg) over the 7-day infusion period, and that effect was blocked in IL-6 KO mice (119±7 to 126±7 mm Hg). RBF decreased to an average of 61±8% of control over the 7-day period (control: 0.86±0.02 mL/min) in the WT mice; however, the average decrease to 72±6% of control (control: 0.88±0.02 mL/min) in the KO mice was not significantly different. There also was no difference in afferent arteriolar constriction by Ang II in blood-perfused juxtamedullary nephrons in WT versus KO mice. Phosphorylation of janus kinase 2 and signal transducer and activator of transcription 3 in renal cortex homogenates increased significantly in Ang II-infused WT mice, and that effect was prevented completely in Ang II-infused IL-6 KO mice. These data suggest that IL-6-dependent activation of the renal janus kinase 2/signal transducer and activator of transcription 3 pathway plays a role in Ang II hypertension but not by mediating the effect of Ang II to decrease total RBF.

FIGURE 1

Mean arterial pressure (mean±SEM) in WT and IL-6 KO mice infused with angiotensin II (AngII) at 800 ng/kg/min and in control WT and KO mice during the control (C) period and AngII treatment (T) period. * = p < 0.05 vs baseline (within-group).

FIGURE 2

Renal blood flow expressed as percent control (mean±SEM) in WT and IL-6 KO mice during the control (C) period, AngII treatment (T) period, and recovery (R) period. WT mice were infused with AngII at 200, 800, or 3600 ng/kg/min, and the IL-6 KO mice were infused with AngII at 800 ng/kg/min. * = p < 0.05 vs baseline (within-group); § = p < 0.05 vs. 800 dose (between-group); # = p < 0.05 vs. 3600 dose (between-group).

FIGURE 3

Afferent arteriole diameter in blood-perfused juxtamedullary nephrons from WT and IL-6 KO mice in response to AngII. * = p < 0.05 vs control (within-group).

FIGURE 4

JAK2 and STAT3 phosphorylation in control WT mice, AngII infused WT mice (800 ng/kg/min), control IL-6 KO mice, and AngII infused IL-6 KO mice (800 ng/kg/min). * = p < 0.05 vs control.