Abstract P456: Loss of Renal Resident Tissue Macrophages Reduces Nitric Oxide-Mediated Relaxation during Salt-Sensitive Hypertension

Salt-sensitive hypertension (SS-HTN) associates with increased renal sodium reabsorption, arterial dysfunction, and heightened pro-inflammatory cytokines such as interleukin 6 (IL-6). Renal resident tissue macrophages (rRTMs) function to both maintain tissue homeostasis and once activated, can secrete IL-6. We reported that loss of the rRTM population prevents SS-HTN but their influence on arterial reactivity has not been tested. We hypothesize that rRTM-induced IL-6 production impairs endothelial function. Wild-type (Wt) or rRTM-depleted (CX3CR1-EGFP+/+) male mice (12wks) were used. Mice were given the nitric oxide synthase (NOS) inhibitor, L-NAME (0.5mg/mL, in drinking water, 2wks) and allowed to washout (1-2wks) before fed normal chow (NC), high salt (HS) chow (4%) for 2 days (early salt-sensitive, eSS) or for 3wks HS (SS-HTN). eSS mice were salt-sensitive, but not yet hypertensive. Mice were also given HS chow alone (3wks). Serum was collected for systemic cytokines (Meso-Scale Discovery; n=4-15) and second-order mesenteric resistance arteries (MRAs) were obtained (n=3-5). Concentration response curves (CRCs) to phenylephrine (Phe) and acetylcholine (ACh) were performed in the presence or absence of potassium chloride (KCl) or L-NMMA. Serum IL-6 levels were not increased following HS diet alone, but concentrations trended higher during SS-HTN (1.46 ± 0.2 pg/mL vs. 1.07 ± 0.2 pg/mL NC). The nadir was observed in eSS mice, before the development of SS-HTN, and was prevented in rRTM-depleted mice (1.81 ± 0.3 pg/mL vs. 0.58 ± 0.17, **p<0.001, grouped ANOVA). No differences were observed between NC-fed Wt and rRTM-depleted MRAs, but the development of SS-HTN did impair relaxation responses. Overall, ACh-mediated relaxation responses were generally lower in MRAs from rRTM-depleted mice compared to Wt. Interestingly, rRTM-depleted MRAs from SS-HTN animals exhibited a near complete inhibition of all relaxation responses with NOS inhibition (Rmax 6.20% ± 8 rRTM SS-HTN vs. 63.0% ± 10 Wt SS-HTN, *p<0.05), suggesting greater dependence on NO-mediated relaxation. Together, these data suggest that rRTMs contribute to an early, hypertension-independent spike in IL-6 which may reduce endothelial function later during SS-HTN. We also show that rRTM-depletion affects the function of the resistance vasculature, including loss of non-NO-mediated relaxation during SS-HTN. These data suggest that renal-derived cytokines, via rRTMs, may influence endothelial function.