Autosomal Dominant Polycystic Kidney Disease is the most common monogenetic disorder, affecting 500,000 people in the United States alone. The disease presents clinically in the third decade of life and on average and results in end-stage renal disease by the fifth decade, leading to long-term dialysis and, ultimately, kidney transplantation. To date, there have been several proposed pharmaceutical agents that have shown success in animal studies at maintaining kidney integrity. However, due to disappointing and spurious data from several clinical trials involving these small molecule inhibitors there is currently no pharmacological intervention available as a treatment that has been approved for patients in the United States. Reasons for the lack of translational success in human trials include inadequate dosing, low patient compliance, the cost of administration, and the impractical nature of long-term drug treatment. Therefore, future proposed treatments warrant the exploration of alternative delivery methods and approaches in the regulation of these downstream biological targets.

HDAC inhibition slows disease progression with no clear relationship to polycystin-1 (PC1) activity. I report here that the carboxyl-terminal tail of PC1 interacts with at least two acetyl transferases, p300/CBP Associated Factor (P/CAF) and alpha-Tubulin Acetyl Transferase (alphaTAT1). Using an antibody against acetylated lysine, the cytoplasmic carboxy-terminal tail fragment of PC-1 is constitutively acetylated and this signal is dependent on a region of the protein that lacks any lysine residues. Mutations to conserved lysine residues increased transcription factor signaling, while a single mutation in the interaction region disrupts this signaling. This data would support PC-1 activity acting as a counter-balance to the activity of HDACs, and thereby provide a potential explanation for success found in the use of HDAC inhibitors on the disease.

Previous work in our lab has demonstrated that direct targeting of the folate-receptor by drug conjugation with a disulfide linker can ameliorate the disease to the same extent as the unconjugated drug itself. To further this investigation, we demonstrate direct receptor occupancy of folate-conjugated drug surrogates on the cyst-lining epithelial cells in PKD animal tissue. We also find equal efficacy with a folate-conjugated form of Rapamycin to its unconjugated analogue. Furthermore, we determine that there is a dosing window where conjugation limits the gross side-effects of rapamycin treatment and specifically targets the kidney. Within this window the conjugated form of rapamycin targets renal tissue at the molecular level over at least a three-fold window before seeing a decrease in efficacy while the unconjugated form continues to affect extra-renal tissues even at doses that begin to lose efficacy in the treatment of the disease. This work furthers the field by demonstrating that a targeted treatment approach using small molecule inhibitors is possible by increasing the effective dose at the site of the tissues and eliminating extra-renal side effects.

Finally, analysis of comparative signaling patterns to proposed drug treatments in ADPKD suggested that an alternative treatment through reduced-food intake could effectively slow kidney growth and ameliorates disease progression. A mild reduction in food intake in an orthologous animal model of ADPKD significantly reduced kidney growth, decreased the occurrence of end-stage renal disease, and decreased the accumulation of fibrotic interstitial tissue. As a consequence of treatment, signaling through mammalian target of rapamycin was reduced, presumably through the activation of upstream negative regulators. This change was seen without a statistically significant change in animal growth over time and no outward negative side effects. This study suggests the need for clinical evaluation of reduced food intake as a treatment option for patients with the disease. Collectively, this work advances our understanding of the signaling associated with PC-1, brings together this activity with a variety of the inhibitors that have shown success in the treatment of the disease, advances the potential for these treatments in a long-term targeted approach, and proposes a comprehensive alternative to pharmaceutical intervention.