ABSTRACT Chronic overactivity of renal nerves results in physiological and pathological changes in renal function that contribute to kidney-based diseases. Hypertension is correlated with increased activity of sympathetic nerves to the kidneys in preclinical models, and in most of these models, hypertension is attenuated by renal denervation (RDN). Clinical trials building on these models have demonstrated that catheter-based RDN is effective in lowering arterial pressure in hypertensive patients. The success of catheter-based RDN to treat hypertension has catalyzed the emerging field of electroceuticals, which is based on the concept of organ-specific neuromodulation (rather than ablation) for cardiometabolic diseases. Whereas ablation is non-reversible and non-tritratable, neuromodulation can be incorporated into a closed-loop feedback design to precisely regulate the activity of nerves as desired. Moreover, neuromodulation can be turned off and restarted as needed. Combined, our laboratories have extensive knowledge on the role of renal nerves in the pathogenesis of hypertension and the mechansims mediating the anti-hypertensive effect of RDN in rodent models (Co-PI Osborn) as well as experience in developing computational modeling tools to design neurotechnologies (Co-PI Johnson. We aim to translate this knowledge to the development of a novel implantable technology for neuromodulation of the kidney for treatment of neurally-mediated renal pathology in a translational large animal model of renal pathology (DOCA-salt sheep). In Specific Aim 1, we will develop a bidirectional renal nerve cuff interface, first in silico and then in the lab, to electrically block (E-Block) and sense (E-Sense) renal nerve activity in sheep. In Specific Aim 2, we will optimize stimulus parameters of renal E-block in vivo by comparing the acute renal responses to E-Block to those observed following surgical ablation in anesthetized DOCA-hypertensive sheep. Successful development of this neuromodulatory tool for treatment of renal disease can be translated to treat other chronic diseases associated with overactivity of renal nerves including chronic kidney disease and end-stage renal failure. Moreover, this same technology can potentially be used to modulate other organs (e.g. liver, pancreas, spleen) for the treatment of chronic cardiometabolic diseases that are linked to excessive nerve activity.