Molecular pathogenesis of ADPKD and development of targeted therapeutic options.

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease characterized by formation and progressive enlargement of cysts in kidneys, liver and other organs, leading to end stage renal disease by the fifth decade [1]. Mutations in the PKD1 gene encoding polycystin-1 are responsible for 85% of ADPKD cases, while mutations in the PKD2 gene cause 15% of ADPKD cases with a less severe phenotype. Autosomal recessive polycystic kidney disease (ARPKD) affects newborns and results from mutations in the PKHD1 gene encoding fibrocystin [2]. Regardless of the genetic defect underlying PKD, cystic epithelia seem to display common abnormalities. Cellular mechanisms of cystogenesis have been studied for decades and suggest that cystic epithelia are characterized by a secretory phenotype with increased proliferation, apoptosis, loss of cellular differentiation and polarity. Considerable progress towards understanding the molecular pathogenesis of cyst formation has been made since the cloning of the PKD1 and PKD2 genes as well as other cystogenes responsible for multiple forms of PKD in animal models. Based on the enhanced understanding of the signalling pathways involved in cystogenesis, novel therapeutic approaches targeting mTOR activity, and cAMP activated signalling pathways are being tested in the clinic [3]. Also, recent studies highlight the importance of the primary cilium as a common trigger of cystic diseases [4]. The molecular link between cilia, mechanosensation and the cell cycle can now be explored for novel targeted therapeutic intervention in PKD. Here we focus on reviewing recent advances in understanding the molecular pathways of cystogenesis and therapeutic approaches to interfere with these pathways in preclinical and clinical trials.