Abstract 005: Loss of Interleukin 21 Protects Against Hypertension and Associated Inflammation and End Organ Damage

Abstract

T cell derived cytokines such as interferon gamma (IFNγ) and interleukin 17A (IL17A) are upregulated by and can promote angiotensin II-induced hypertension and end-organ damage. Interleukin 21 (IL21) is produced primarily by T follicular helper (Tfh) cells and has the potential to promote IL17A and IFNγ production from T effector cells while inhibiting T regulatory cells. IL21 is also a potent activator of germinal center (GC) B cells. Thus, we hypothesize that IL21 promotes hypertension and hypertensive end-organ damage through its effect on T cell polarization and GC B cell activation. The data indicate that indeed IL21 -/- mice exhibit a 30 mmHg reduction in blood pressure in response to 4 weeks of angiotensin II (Ang II) infusion compared to age-matched wild type (WT) mice (p=0.0275). IL21 mRNA expression increases 1.5 fold in splenic T cells in response to Ang II infusion (p=0.015). Moreover, Tfh cells and GC B cells are increased in the aortas of WT mice after Ang II infusion (p=0.0136 and p=0.0067, respectively). Further, IL17A production from splenic CD4+ T cells and IFNγ production from splenic CD8+ T cells was reduced in IL21 -/- mice compared to WT mice (p=0.0025 and p=0.0237, respectively) following Ang II infusion. Renal function was assessed by measuring albuminuria. WT mice developed 2-fold more albuminuria compared to IL21 -/- mice in response to Ang II infusion (p=0.0349). Lastly, Ang II infusion impaired endothelium-dependent relaxation to acetylcholine in mesenteric vessels from WT mice (52.9% vs 17.5%; p=<0.0001). IL21 -/- mice demonstrated moderately impaired endothelium-dependent relaxation at baseline (34.9%) but interestingly, there was no further impairment in these vessels following Ang II infusion. Taken together, these studies suggest that IL21 and the Tfh cell–GC B cell axis may play a key role in hypertension and hypertensive end-organ damage.