Abstract 169: Activation of The Interleukin-1 Receptor Contributes to the Pathogenesis of Angiotensin II-dependent Hypertension by Regulating Sodium Excretion
Interleukin 1(IL-1) is an important regulator of inflammation and innate immunity and exerts diverse actions in multiple tissue beds. Previous studies have found increased renal IL-1 production in the setting of angiotensin (Ang) II-induced hypertension. The current study therefore explored whether activation of the IL-1 receptor (IL-1R) contributes to the pathogenesis of Ang II-dependent hypertension. Thus, we chronically infused uni-nephrectomized IL-1R-deficient (IL-1R KO) mice and wild-type (WT) controls (n=9 per group, 129/SvEv strain) with Ang II (1000ng/kg/min) for 4 weeks. At baseline, the mean arterial blood pressure (MAP) was similar in WT and IL-1R KO mice (131±9 vs. 125±6 mm Hg; p=NS). By contrast, after the 1st week of Ang II infusion, IL-1R KO mice had markedly attenuated elevations in BP (169±6 vs.184±3 mm Hg; p<0.05). Consistent with their lower BPs, IL-1R KO mice had smaller heart weight/body weight ratios compared to WTs after Ang II infusion for 14 days (7.4±0.2 vs. 6.7±0.3 mg/g, p=0.058) and 28 days (9.3±0.8 vs. 7.5±0.9 mg/g, p<0.001). Moreover, Ang II-infused IL-1R KOs had nearly 40% less albuminuria than WTs (5.9±0.9 vs. 9.4±1.4 mg/mg Cr; p=0.05). Consistent with reduced renal damage in the Ang II-infused IL-1R KOs, this group had lower renal mRNA expression of the kidney injury marker NGAL than Ang II-infused WTs (0.37±0.06 vs. 1.00±0.19 au; p=0.008) whereas expressions of IL-1α and β were similar in the 2 groups. Levels of urinary sodium excretion were similar in the groups at baseline and during the 1st week of Ang II when BPs were also similar. However, during the 2nd week of Ang II when BPs started to diverge between the groups, the IL-1R KOs excreted 23% more sodium than WT controls (416±23 vs. 337±25 μmol/day; p<0.04) while daily food intake was virtually identical in the groups throughout the experiment. As IL-1 has known vascular effects and renal blood flow can impact sodium excretion, we then examined acute pressor responses to Ang II (100ng) after 2 weeks of chronic Ang II infusion. The pressor response was blunted by 25% in IL-1R KOs compared to WT controls (30±2 vs. 41±4 mm Hg, p=0.04). We conclude that activation of the IL-1R potentiates Ang II-dependent hypertension by enhancing vasoconstriction and thereby limiting sodium excretion.
- © 2012 by American Heart Association, Inc.