IL-1R Mediated Activation of Renal Sensory Nerves in DOCA-Salt Hypertension

BACKGROUND:Clinical trials of renal denervation for the treatment of hypertension have shown a variety of off-target improvements in conditions associated with sympathetic overactivity. This may be due to the ablation of sympathoexcitatory afferent renal nerves, which are overactive under conditions of renal inflammation. Renal IL (interleukin)-1 beta is elevated in the deoxycorticosterone acetate-salt model of hypertension, and its activity may be responsible for the elevation in afferent renal nerve activity and arterial pressure.METHODS:Continuous blood pressure recording of deoxycorticosterone acetate-salt mice with IL-1R (IL-1 receptor) knockout or antagonism was used individually and combined with afferent renal denervation (ARDN) to assess mechanistic overlap. Protein quantification and histological analysis of kidneys were performed to characterize renal inflammation.RESULTS:ARDN attenuated deoxycorticosterone acetate-salt hypertension (-20 +/- 2-Delta mm Hg mean arterial pressure [MAP] relative to control at study end) to a similar degree as total renal denervation (-21 +/- 2-Delta mm Hg MAP), IL-1R knockout (-16 +/- 4-Delta mm Hg MAP), or IL-1R antagonism (-20 +/- 3-Delta mm Hg MAP). The combination of ARDN with knockout (-18 +/- 2-Delta mm Hg MAP) or antagonism (-19 +/- 4-Delta mm Hg MAP) did not attenuate hypertension any further than ARDN alone. IL-1R antagonism was found to have an acute depressor effect (-15 +/- 3-Delta mm Hg MAP, day 10) in animals with intact renal nerves but not those with ARDN.CONCLUSIONS:These findings suggest that IL-1R signaling is partially responsible for the elevated afferent renal nerve activity, which stimulates central sympathetic outflow to drive deoxycorticosterone acetate-salt hypertension.