Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II–Induced Hypertension

stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues. Objective: To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension. Methods and Results: Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II–induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4 + and CD8 + T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1 α , IL-1 β , and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II–treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation. Conclusions: Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension. ( Circ Res . 2015;117:547-557. DOI: 10.1161/CIRCRESAHA.115.306010.) sympathetic nerves and their release of norepinephrine. RDN reduces activation of dendritic cells and ultimately T cells and thus prevents both renal and vascular inflammation. Our findings may help explain why RDN has pleiotropic systemic effects. Magnetic Resonance Imaging: Relative renal blood flow (rRBF) and relative renal blood volume (rRBV) were measured by dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with the administration of iron oxide nanoparticles as described. 8, 9 Six mice with unilateral renal denervation and two-week angiotensin II infusion were used in this experiment. One or two days before of scanning, a catheter was placed in the jugular vein, and externalized from the interscapular region for administration of contrast agent. Mice were anesthetized (isoflurane 1.5-2%) and scanned on a Varian 7T MRI system using a Doty 38 transmit/receive coil. Body temperature was maintained at 37° during the scan. An oblique axial plan through both kidneys was chosen. A dynamic susceptibility-weighted gradient-echo sequence was applied during an iv injection of monocrystalline iron oxide nanoparticles (MION, 6mg/kg), which was administered rapidly in less than one second. A dynamic series of 600 images (~1s/volume) was acquired up to 10 minutes. R 2 imaging was performed using a multiple spin echo sequence with refocusing pulses of 180 (repetition time=2500ms, 16 echoes, 4 averages) before and after MION injection. The averaged ΔR 2 across voxels of each kidney was used to represent rRBV, while peak amplitude/area from the relative DSC signal intensity time curve of each kidney was used to represent rRBF (sec -1 ). of differences in Bonferroni correction for comparisons of cytokine release by DCs. P values in the figures and a than