Preclinical validation and mechanistic understanding of drug repurposing candidates for polycystic kidney disease

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common cystic kidney disease worldwide, affecting 1:400 to 1:2500 people worldwide. ADPKD is characterized by the formation of renal cysts, which grow over time in both size and number. ADPKD is caused by mutations in the PKD1 or PKD2 gene. Until now, the vasopressin V2 receptor antagonist tolvaptan is the only available ADPKD therapy, but tolvaptan has side effects like polyuria and hepatotoxicity, limiting its use to only a subset of patients. In this thesis, we have employed a drug repurposing strategy, in which we have tested various existing medications for other indications in conditional Pkd1 knock-out mouse models. The results described in this thesis have identified the AMP-activated protein kinase (AMPK) activator salsalate as a candidate for possible use as an ADPKD therapeutic. This research might ultimately lead to the development of salsalate, and potentially other medications, as a treatment option for ADPKD patients.