Afferent renal nerve activity response to IL-6 and IL-1ß antagonism in the DOCA-salt rat model of hypertension
Authors: AlMarabeh Sara , Leung Christian , Smith Beatriz , Banek Christopher 
Published: May 2023

Hypertension is the highest risk factor for cardiovascular disease, which remains the leading cause of death worldwide. Though hypertension is a multifaceted disease, there is an increasingly clear role for renal nerves in hypertension progression – both sympathetic and afferent. Moreover, afferent renal nerve activity (ARNA) is reportedly elevated in several models of hypertension and hypothesized to be a major contributor to the disease etiology. Yet, the underlying stimulus for this increased activity is unknown. Previous studies from our lab highlighted a direct correlation between ARNA and renal proinflammatory cytokine content in hypertensive rats, specifically IL-6 and IL-1ß. Therefore, we aimed to acutely disrupt IL-6 and IL-1ß activity to elucidate the direct effects on ARNA in hypertension. We hypothesized that antagonism of IL-6 and IL-1ß will decrease ARNA in hypertensive rats. To address this hypothesis, we employed the deoxycorticosterone acetate (DOCA)-salt model of hypertension. Briefly, uninephrectomized male Sprague Dawley rats (275-325g, n=3) were administered DOCA (100 mg, s.c) and saline drinking water (0.9% NaCl) for three weeks. Next, rats were surgically prepared for renal nerve activity measurement and administration of cytokine antagonists. Under anesthesia (Urethane, 1800 mg/kg/h, IV), a renal nerve bundle of the left kidney was hooked with a bipolar electrode. Renal sympathetic nerve activity (RSNA) was rectified and integrated to identify burst rate. To isolate the ARNA, the proximal end of the nerve bundle was cut and nerve activity was rectified and integrated over 50 ms. Basal ARNA was normalized to peak ARNA response to 5 μl capsaicin (10 μg/μl). To suppress IL-6 and IL-1ß intrarenally, 10 μl of IL-6 antibody (0.1 μg/μl) and 10 μl of IL-1ß antibody (0.1 μg/μl) were injected into the renal artery. Vehicle (saline) injections were used as control. ARNA was recorded for 10 mins after injections and expressed as percentage of baseline (%ARNABase). Data were analyzed by repeated measures one-way ANOVA with Dunnett post hoc test vs. vehicle (*p<.05) and presented as mean±SEM. At time of acute surgical preparation, mean arterial blood pressure was 152±1mmHg. Basal RSNA was 5.4±0.6bursts/s and 1.5±0.26bursts/beat. Resting ARNA was 9.5±2.8%ARNAMAX. Compared to the response to vehicle administration (84.4±8.0 %ARNABase), IL-6 antibody decreased ARNA to *49.8±6.9 %ARNABase. No difference in IL-1ß antibody response (53.6±15.4 %ARNABase, P>.05) was detected compared to vehicle. These preliminary results partially support our hypothesis that antibody-mediated suppression of renal IL-6 acutely lowers ARNA in hypertensive DOCA-salt rats. This highlights that increased ARNA in the hypertension may be driven in part by direct stimulation from proinflammatory cytokines such as IL-6. Further studies are underway to increase sample size, include female cohorts, and measure the effects of antibody treatment in normotensive controls. R00HL141650 (CTB), Doris Duke Charitable Foundation (CTB) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.