Abstract 022: Role of Interleukin-17 in the Regulation of Hemodynamics and Renal Sympathetic Nerve Activity in Rats

Abstract

Introduction: Central inflammation has been implicated in the pathophysiology of hypertension (HTN) and heart failure (HF). We previously reported that the pro-inflammatory cytokines (PIC) tumor necrosis factor-α and interleukin (IL)-1β act within the brain to increase blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) and contribute significantly to the neurohumoral activation in these diseases. Over the years, IL-17A, a PIC secreted mainly by Th17 cells and γδ T cells, has been identified as a critical inflammatory mediator promoting chronic inflammation in cardiovascular diseases. Growing evidence indicates that IL-17A penetrates the blood-brain barrier and that its receptors, IL-17RA and IL-17RC, are abundantly expressed in CNS. However, whether IL-17A contributes to sympathetic excitation remains unknown. Hypothesis: IL-17A acts centrally to influence sympathetic drive and cardiovascular dynamics. Methods: BP (mmHg), HR (bpm) and RSNA (% change) were recorded in urethane anesthetized male Sprague Dawley rats. IL-17A was administered by intravenous (IV, 500 ng) or intracerebroventricular (ICV, 100 ng) injection or by bilateral microinjection (25 ng/side) into hypothalamic paraventricular nucleus (PVN). IL-17RA expression in the PVN was visualized by confocal microscopy. Results: IV IL-17A (n=6) induced a substantial and long-lasting increase (*p<0.001 vs. baseline) in BP (16.7 ± 2.1*), HR (57 ± 8*) and RSNA (104.5 ± 4.8 %*), that began within 45-60 mins and peaked 5-6 hours after IV injection. Similarly, ICV (n=6) or PVN microinjection of IL-17A (n=6) elicited dramatic and long-lasting increases in BP (23.1 ± 2.5 and 19.6 ± 2.1, respectively), HR (78.6 ± 7.4 and 65.1 ± 6.8, respectively) and RSNA (223.6 ± 5.1 and 152.2 ± 3.3, respectively), with the peak responses at 5 to 6 hours or even later. Confocal images showed that IL-17RA was richly expressed in the PVN. Conclusion: These data demonstrate that IL-17A regulates cardiovascular function and sympathetic drive, suggesting that IL-17A may contribute to sympathetic excitation in chronic inflammatory conditions like HTN and HF via its actions within the brain. IL-17A is a potential target for therapeutic intervention in these diseases.