PROJECT SUMMARY Catheter-based renal nerve ablation (CBRNA) decreases blood pressure (BP) and disrupts the chronic overactivity of sympathetic efferent renal nerves thought to underlie neurogenic hypertension (HTN), diminishing the risk for developing other cardiometabolic diseases. Studies have demonstrated that a contributor to the development of neurogenic HTN is sensory afferent renal nerves (ARNs) whose input to central autonomic regions modulates sympathetic outflow to other organs. Recent work from our lab has identified the close proximity of ARNs to glomeruli in the renal cortex, which is novel in comparison to the traditional view that ARNs primarily innervate the renal pelvis. The implication of ARNs in regulating BP and the identification of ARNs in the renal cortex indicates the need for the role of ARNs in kidney function and autonomic processes to be investigated. This proposal aims to address this gap in knowledge by 1) elucidating the central terminations and regional specificity of renal afferents, and 2) identifying how renal afferent input influences the activity of central autonomic regions that regulate blood pressure using a salt-induced model of hypertension. Aim 1 will use viral vector-based neurotracing to label ARNs from the renal cortex and renal pelvis of the kidney to identify their central terminations. I hypothesize that two distinct populations of ARNs innervate the renal cortex and pelvis respectively, and project to distinct primary central termination sites. Tracing will be visible throughout the neuroaxis including the renal vasculature, dorsal root ganglia, nodose ganglia, spinal cord, and brainstem. Aim 2 will be completed using the deoxycorticosterone acetate (DOCA)-salt mouse model, which induces HTN through sodium and water retention, in targeted recombination of active populations (TRAP2) mice where the fluorescent reporter protein tdTomato is expressed under the immediate-early gene c- Fos, a neuronal activation marker, via tamoxifen-inducible Cre. The expression of tdTomato will be quantified as a direct measure of c-Fos in brain regions known to be involved in BP regulation during early DOCA-salt HTN development and compared to immunolabeled c-Fos at a later timepoint. I hypothesize that DOCA will increase the expression of tdTomato and c-Fos in non-denervated mice, and that afferent renal denervation (ARDN) and an IL-1 receptor antagonist will both attenuate the DOCA-induced neuronal activity. The expected outcomes of this proposal are to have traced the terminals of ARNs from the kidney to central primary processing centers and identified changes in neuronal activation in central autonomic centers relevant for ARN processing. These results will expand the understanding of how ARNs are involved in salt-induced HTN and establish an anatomical foundation for future investigations into the physiological roles of ARNs in the autonomic control of BP regulation. Further, these findings may contribute to th...