Greater IL-33 in female DOCA-salt rats contributes to lower blood pressure vs. males

Hypertension affects 50% of U.S. adults and remains the leading cause of premature death. A barrier to improved blood pressure (BP) control is the limited understanding of mechanisms that differentially regulate BP in males and females. T cells contribute to BP regulation, with effector T cells promoting and regulatory T cells (Tregs) limiting hypertension. We have previously shown that females have more Tregs and lower BP than males, but the mechanisms driving these sex differences remain unclear. Hypertension triggers inflammation through damage-associated molecular patterns, including IL-33, whose actions depend on its receptor ST2. IL-33 signaling through transmembrane ST2 (t)ST2 promotes anti-inflammatory responses and Treg development, activation, and expansion, whereas soluble ST2 (sST2) neutralizes IL-33 to abolish the protective actions of IL-33. Whether IL-33 and sST2 differ between males and females, and whether sex hormones regulate sST2, has not been defined. Additionally, how IL-33 differentially influences BP control between males and females remains uncertain. This study was designed to test the hypothesis that greater Treg abundance in females is accompanied by higher IL-33 that contributes to their lower BP. We further hypothesized that females have lower sST2 and that sST2 levels are mediated by sex hormones. Male and female Sprague-Dawley rats were uni-nephrectomized (UNX) and randomized to deoxycorticosterone acetate (DOCA)–salt (200mg s.c) or control for 3 weeks (n=6/group). To assess the role of IL-33 in BP regulation, additional DOCA-salt rats were implanted with telemeters for BP measurement and randomized to treatment with either an IL-33 neutralizing antibody (250 µg/rat, i.p) or IgG control (n=3/group). To examine hormonal regulation of sST2, additional subsets of rats underwent gonadectomy (GDX) at 5 wks. of age before UNX/DOCA at 12 weeks (n=5/group). All rats were euthanized 3 weeks after treatment, and plasma and kidneys were collected. Renal IL-33 was quantified by Western blot and plasma sST2 was measured by ELISA. Control females had greater renal IL-33 levels than males (Psex 0.05), abolishing the sex difference in BP. Plasma sST2 levels were greater in males vs. females (PSEX =0.0002). DOCA increased sST2 (PDOCA< 0.0001), and the increase was greater in males (Psex*DOCA=0.02). GDX reduced sST2 in DOCA-treated males (P=0.02), but increased sST2 in DOCA-treated females (P< 0.0001), indicating hormonal control of sST2 in DOCA-salt hypertension. Taken together, our data indicate that greater Treg abundance in females is accompanied by greater IL-33, which contributes to the lower BP in DOCA-salt females. Importantly, sST2 levels are greater in males and hormonally regulated in both sexes. Ongoing studies will determine whether IL-33-dependent BP regulation in females is mediated by Tregs. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.