Targeting Cyst Initiation in ADPKD

Abstract

With approximately 12.5 million people worldwide affected by autosomal dominant polycystic kidney disease (ADPKD), one hopes we are now at the beginning of multiple therapeutic breakthroughs. ADPKD is a hereditary disorder caused by a genetic defect in either polycystin-1 ( PKD1 ; PC1) or polycystin-2 ( PKD2 ; PC2) that leads to progressive kidney cyst formation and enlargement. The resulting high cystic burden in the kidney destroys the normal parenchyma and ultimately results in ESRD for the majority of patients. Although many of the cellular events leading to cystogenesis are not yet identified, the process can be roughly divided into the following stages after somatic inactivation of the remaining normal PKD allele through loss of heterozygosity: Loss of calcium-mediated cellular quiescence leading to an initial proliferative phase of tubule epithelial cells; out-pocketing of the tubule wall and eventual cyst separation from the parent nephron; and continued cell growth, fluid secretion, and progressive expansion of isolated cysts. Tremendous progress has been made in understanding the various biologic mechanisms responsible for these pathologic stages of cyst formation and growth that range from the identification of the primary cilia as a mechanosensor mediating PC1/PC2 calcium influx to various perturbations of fluid regulation and cell proliferation. Because many proteins associated with these processes have been identified, we have multiple cellular targets to examine for pharmacologic intervention strategies, some of which are already under investigation. When considering the stages of cystogenesis as described already, it is clear that many small molecule therapeutic agents have focused on cysts that are in the continued growth and expansion phase or the isolated cyst. There are several promising agents that either are under development or are already in clinical trials to reduce the …