Angiotensin II Induces Interleukin-6 in Humans Through a Mineralocorticoid Receptor–Dependent Mechanism

Abstract

This study tested the hypothesis that angiotensin promotes oxidative stress and inflammation in humans via aldosterone and the mineralocorticoid receptor. We measured the effect of intravenous aldosterone (0.7 mug/kg per hour for 10 hours followed by 0.9 mug/kg per hour for 4 hours) and vehicle in a randomized, double-blind crossover study in 11 sodium-restricted normotensive subjects. Aldosterone increased interleukin (IL)-6 (from 4.7+/-4.9 to 9.4+/-7.1 pg/mL; F=4.94; P=0.04) but did not affect blood pressure, serum potassium, or high-sensitivity C-reactive protein. We next conducted a randomized, double-blind, placebo-controlled, crossover study to measure the effect of 3-hour infusion of angiotensin II (2 ng/kg per minute) and norepinephrine (30 ng/kg per minute) on separate days after 2 weeks of placebo or spironolactone (50 mg per day) in 14 salt-replete normotensive subjects. Angiotensin II increased blood pressure (increase in systolic pressure: 13.7+/-7.5 and 15.2+/-9.4 mm Hg during placebo and spironolactone, respectively; P<0.001 for angiotensin II) and decreased renal plasma flow (-202+/-73 and -167+/-112 mL/min/1.73 kg/m(2); P<0.001 for angiotensin II effect) similarly during placebo and spironolactone. Spironolactone enhanced the aldosterone response to angiotensin II (increase of 17.0+/-10.6 versus 9.0+/-5.7 ng/dL; P=0.002). Angiotensin II transiently increased free plasma F(2)-isoprostanes similarly during placebo and spironolactone. Angiotensin II increased serum IL-6 concentrations during placebo (from 1.8+/-1.1 to 2.4+/-1.4 pg/mL; F=4.5; P=0.04) but spironolactone prevented this effect (F=6.4; P=0.03 for spironolactone effect). Norepinephrine increased blood pressure and F(2)-isoprostanes but not aldosterone or IL-6. Aldosterone increases IL-6 in humans. These data suggest that angiotensin II induces IL-6 through a mineralocorticoid receptor-dependent mechanism in humans. In contrast, angiotensin II-induced oxidative stress, as measured by F(2)-isoprostanes, is mineralocorticoid receptor independent and may be pressor dependent.

Comparative Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin-Receptor Blockade on Inflammation during Hemodialysis

“…12 In our study, valsartan and ramipril reduced the levels of IL-6 and IL-8 during hemodialysis. Angiotensin II stimulates IL-6 production and release [31][32][33] ; therefore, ramipril and valsartan have likely reduced IL-6 by preventing the formation or action of angiotensin II. The finding that ramipril treatment increased levels of IL-1b and decreased IL-10, an anti-inflammatory cytokine, however, suggests that ramipril had an additional proinflammatory effect.…”

Selective Mineralocorticoid Receptor Blocker Eplerenone Reduces Resistance Artery Stiffness in Hypertensive Patients

“…8,31 In humans, intravenous infusion of angiotensin II increased circulating concentrations of inflammatory cytokines through a mineralocorticoid receptor-dependent mechanism. 32 Aldosterone induced the synthesis of the inflammatory cytokines MCP-1 and osteopontin directly, 31 promoting vascular inflammation and remodeling, as well as development of atherosclerosis. bFGF has long been recognized to stimulate proliferation of cultured fibroblasts, endothelial cells, smooth muscle cells, and skeletal myoblasts and is also involved in regulation of cell survival, migration, and extracellular matrix production or degradation.…”

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

“…In addition, the amount of IL-6 measured in serum in response to the mineralocorticoid (1.8 pg/mL) probably was not biologically significant, as at least 10 pg/mL are necessary in most standard bioassay systems. Thus, such data should be considered more as suggestive of the causal relationship between inflammation and hypertension rather than definitive [74].…”