Polycystic kidney disease (PKD), both autosomal dominant (AD) and autosomal recessive (AR) forms, remains the 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-function mutation in the polycystin in ADPKD and fibrocystin gene in ARPKD, there remains no cure for these diseases beyond kidney transplantation. Vasopressin (AVP) signaling blockade has been demonstrated to blunt cyst formation, specifically through pharmacological targeting of AVP receptor type 2 (V2R) with Tolvaptan. While V2R antagonism may benefit the patient by delaying cyst and renal disease progression, chronic V2R blockade often leads to a decrease in quality of life due to symptoms such as polydipsia and polyuria. An understudied contributor to hypothalamic regulation of AVP is from the kidney itself, through the renal afferent nerves. With the emergence of catheter-based renal denervation to treat cardiovascular disease, alternative applications of this technique may benefit patient populations with potential aberrant renal nerve signaling. We have recently reported that afferent renal nerve activity (ARNA) is increased over two-fold in an ARPKD model compared to non-cystic controls, and total renal denervation (TRDNx), which disrupts both renal afferent and sympathetic nerve activity, mitigates the cystogenesis and lowers arterial pressure. In addition, targeted ablation of only renal sensory (i.e. afferent) nerves (ARDNx) had a similar abrogating effect on cystogenesis, which highlights the intriguing and novel role of renal nerves in the pathogenesis of this this model. While these data are promising, the mechanisms mediating these responses remain unclear and require further investigation. Critically, we aim to elucidate the role and mechanisms by which renal nerves contribute to AR- and ADPKD. The following aims form the experimental basis of this research proposal: (1) Determine the role of renal nerves in the progression of renal cystogenesis and neurohumoral axis in ARPKD. We will perform either complete bilateral or unilateral renal denervations in PCK rats to test the hypothesis that renal nerves contribute to all phases of renal cystogenesis, function, and proliferative signaling in both the early, mid, and late phases of ARPKD. (2) Elucidate the molecular mechanism and consequences of elevated afferent renal nerve activity in ARPKD. We will quantify the excitatory effects of renal inflammatory cytokines to isolate the causes for elevated afferent renal nerve activity in the PCK rat. We will pair these studies with histochemical tracings of neural activation following renal inflammatory stimuli. (3) Investigate the role for renal nerves and interaction with Tolvaptan in ADPKD progression. 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 to dissecting the novel role of renal nerves in PKD pathogenesis, potentially identifying a novel therapeutic modality.

PROJECT NARRATIVE Polycystic kidney disease (PKD) remains the leading cause of inheritable kidney disease, and the fourth leading cause of end stage renal disease. Outside of chronic dialysis or kidney transplant, prophylactic and intervention treatment targets and options remain limited. These studies will directly address the novel role of renal nerves in PKD progression, and potentially offer a new therapeutic mechanism to target for future PKD treatment.