[Inhibitors of intra-cystic secretion: novel therapies in ADPKD (Autosomal Dominant Polycystic Kidney Disease)]

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human renal disorder. Progressive enlargement of the kidneys is due to aberrant proliferation of the cyst epithelial cells, together with accumulation of fluid within the cyst cavities due to transepithelial fluid secretion. Multiple studies have suggested that fluid secretion across ADPKD cyst-lining cells is driven by the transepithelial secretion of chloride, mediated by the apical cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) and specific basolateral transporters. Increased levels of cAMP, probably reflecting modifications in intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor, in mutant renal epithelia, play an important role in the pathogenesis of ADPKD and contribute to both transepithelial secretion of fluid and proliferation of cyst epithelia. For example, cAMP activates the CFTR leading to the stimulation of Cl- secretion into the cyst lumen. This review focuses on the pathophysiology and molecular mechanism of fluid secretion in ADPKD cysts examined during pre-clinical trials of potentially useful drugs for the treatment of this condition.