Polycystic kidney disease (PKD) both autosomal dominant (AD) and autosomal recessive (AR) forms remainsthe leading cause of inheritable kidney disease in adults and children throughout the US as well as worldwide.Though the pathogenesis of renal cyst formation is understood to be driven primarily by a loss-of-functionmutation in the polycystin in ADPKD and fibrocystin gene in ARPKD there remains no cure for these diseasesbeyond kidney transplantation. Vasopressin (AVP) signaling blockade has been demonstrated to blunt cystformation specifically through pharmacological targeting of AVP receptor type 2 (V2R) with Tolvaptan. WhileV2R antagonism may benefit the patient by delaying cyst and renal disease progression chronic V2R blockadeoften leads to a decrease in quality of life due to symptoms such as polydipsia and polyuria. An understudiedcontributor to hypothalamic regulation of AVP is from the kidney itself through the renal afferent nerves. Withthe emergence of catheter-based renal denervation to treat cardiovascular disease alternative applications ofthis technique may benefit patient populations with potential aberrant renal nerve signaling. We have recentlyreported that afferent renal nerve activity (ARNA) is increased over two-fold in an ARPKD model compared tonon-cystic controls and total renal denervation (TRDNx) which disrupts both renal afferent and sympatheticnerve activity mitigates the cystogenesis and lowers arterial pressure. In addition targeted ablation of only renalsensory (i.e. afferent) nerves (ARDNx) had a similar abrogating effect on cystogenesis which highlights theintriguing and novel role of renal nerves in the pathogenesis of this this model. While these data are promisingthe mechanisms mediating these responses remain unclear and require further investigation. Critically we aimto elucidate the role and mechanisms by which renal nerves contribute to AR- and ADPKD. The following aimsform the experimental basis of this research proposal: (1) Determine the role of renal nerves in the progressionof renal cystogenesis and neurohumoral axis in ARPKD. We will perform either complete bilateral or unilateralrenal denervations in PCK rats to test the hypothesis that renal nerves contribute to all phases of renalcystogenesis function and proliferative signaling in both the early mid and late phases of ARPKD. (2) Elucidatethe molecular mechanism and consequences of elevated afferent renal nerve activity in ARPKD. We will quantifythe excitatory effects of renal inflammatory cytokines to isolate the causes for elevated afferent renal nerveactivity in the PCK rat. We will pair these studies with histochemical tracings of neural activation following renalinflammatory stimuli. (3) Investigate the role for renal nerves and interaction with Tolvaptan in ADPKDprogression. We will determine the role for renal innervation and interaction with V2R antagonist Tolvaptan (FDA-approved) in the cystogenesis and renal dysfunction in mouse models of rapid (PKD1-/-) and progressive onset(PKD1rc/rc) of ADPKD. These studies are poised to bring a robust and innovative experimental approach todissecting the novel role of renal nerves in PKD pathogenesis potentially identifying a novel therapeutic modality.