Interleukin 6 Knockout Prevents Angiotensin II Hypertension

Abstract

Chronic angiotensin II (AngII) infusion stimulates IL-6 release, and we and others have shown that preventing the increase in IL-6 significantly attenuates AngII hypertension. This study measured renal blood flow (RBF) chronically, using Transonic flow probes in wildtype (WT) and IL-6 knockout (KO) mice, to determine the role of renal blood flow regulation in that response. AngII infusion at 200, 800, and 3600 ng/kg/min caused a dose-dependent decrease in renal blood flow in WT mice, and the response at 800 ng/kg/min was compared between WT and IL-6 KO mice. AngII infusion increased plasma IL-6 concentration in WT mice and increased MAP (19 hrs/day; DSI telemetry) from 113±4 to 149±4 mmHg (Δ 36 mmHg) over the 7-day infusion period, and that effect was blocked in IL-6 KO mice (119±7 to 126±7 mmHg). 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 AngII in blood-perfused juxtamedullary nephrons in WT vs. KO mice. Phosphorylation of JAK2 and STAT3 in renal cortex homogenates increased significantly in AngII-infused WT mice, and that effect was prevented completely in AngII-infused IL-6 KO mice. These data suggest that IL-6-dependent activation of the renal JAK2/STAT3 pathway plays a role in AngII hypertension, but not by mediating the effect of AngII to decrease total renal blood flow.

Deletion of interleukin-6 prevents cardiac inflammation, fibrosis and dysfunction without affecting blood pressure in angiotensin II-high salt-induced hypertension

“…There is some controversy in the literature over whether or not interleukin-6 contributes to the pressor response in the commonly used mouse model of Ang II-induced hypertension. The above-mentioned study by Lee et al [8] showed an attenuation of the pressor response to Ang II in mice fed 4% NaCl diet, and a blunted pressor response to Ang II was reported in mice fed regular chow as well [9,24]. However, Schrader et al [25] found that C57 and interleukin-6 KO mice had similar increases in BP after 2 weeks of Ang II infusion.…”

Blood pressure-renal blood flow relationships in conscious angiotensin II- and phenylephrine-infused rats

“…Although the acute renal vasoconstrictive effects of ANG II have been extensively documented in rodents, previous studies at single time points after chronic ANG II infusion have failed to show significant RBF reductions in anesthetized or conscious rats, possibly because of the counteracting effects of increased perfusion pressure (67,68,83). Brands et al (13), however, recently reported a reduction of RBF measured over several days in conscious ANG II-infused mice, although the dose of ANG II required to elicit such RBF responses was significantly higher than that administered to rats in the present study, and the effects on time-dependent variability in BP-RBF relationships were not reported. In any event, given the spontaneous and often large fluctuations of arterial BP and RBF that were found in the present study, acute single assessments of hemodynamics may not be sufficient to fully characterize the chronic effects of ANG II on RBF.…”

Loss of Timp3 Gene Leads to Abdominal Aortic Aneurysm Formation in Response to Angiotensin II

“…Ang II is a physiological hormone that is elevated in patients with cardiovascular diseases (41)(42)(43) and has been shown to exert direct effects on vascular remodeling and function in numerous studies (22,44,45). The Ang II infusion model allowed us to examine the role of TIMP3 in the adverse remodeling of the aortic wall leading to aortic aneurysm formation.…”