Abstract Hypertension (HTN) is linked to increased sympathetic nervous system activity (SNA) and increased activity of renal efferent nerves is thought to be important. However, the kidneys are also innervated by renal afferent nerves, which project to central nervous system circuits that modulate SNA to various peripheral targets. As such, increased afferent renal nerve activity (ARNA) is also postulated to contribute to increased SNA and the pathogenesis of HTN. Renal denervation (RDNx) for treatment of HTN in humans is now possible. However, the mechanisms by which RDNx lowers AP remain unknown. An emerging new theory of HTN may provide new insights. It is hypothesized that HTN is caused, in part, by a close relationship between renal nerves, renal inflammation, and HTN. These findings suggest that the antihypertensive response to RDNx is not due to disruption of neural control of renal function per se, but rather, blockade of the interaction of immune cells with efferent and afferent renal nerves. These findings led to the Central Hypothesis of this proposal: DOCA-salt HTN is caused, in part, by the action of proinflammatory cytokines on afferent renal nerves resulting in neurogenically mediated HTN. Four Specific Aims will rigorously test this Central Hypothesis. Specific Aim 1: Investigate the neurophysiological mechanisms by which cytokines modulate ARNA in the DOCA-salt rat. Specific Aim 2: Define the anatomical substrates responsible for modulation of ARNA by immune mediators in DOCA-salt rats and mice. Specific Aim 3: Correlate the hemodynamic mechanisms mediating the anti-hypertensive response to ablation and pharmacological blockade of ARNA in DOCA-salt HTN, to urinary biomarkers of renal inflammation. Specific Aim 4: Employ a novel GCaMP3 mouse ex vivo renal slice preparation to identify molecular targets mediating cytokine modulation of afferent renal nerves in normal and DOCA-salt mice. Identification of the mechanisms by which immune cells interact with renal afferent nerves in HTN will also benefit understanding other renal inflammatory diseases with elevated SNA such as chronic renal failure.