Objectives: 

In autosomal dominant polycystic kidney disease (ADPKD) renal cysts enlarge slowly during the patient's lifetime. Despite the growing cysts, renal function is not typically compromised until midlife but then the decline is precipitous and progresses to renal failure within a few years. Renal injury whether traumatic, chemical or hypoxic exacerbates renal decline. The objective of the studies was to characterize the factors and channels involved in cyst growth during late stage ADPKD. It is our hypothesis that renal injury or natural aging of cysts in ADPKD patients causes cyst rupture thereby releasing factors that accelerate expansion of remaining cysts.

Materials: 

Electrophysiological techniques were used to characterize the ion transport response of normal renal principal cells (mouse principal cells of the kidney cortical collecting duct; mpkCCD) after exposure to cyst fluid from human ADPKD patients.

Results: 

Addition of cyst fluid to the basolateral side of principal cells stimulated a chloride secretory response that, in vivo, would result in cyst expansion. The active component of the cyst fluid is lysophosphatidic acid (LPA). Cyst fluid contains sufficient LPA to maximally stimulate secretory chloride transport. The chloride secretory flux involved ion movement through the cystic fibrosis transmembrane conductance regulator (CFTR) and through an alternative channel with an inhibitory profile consistent with TMEM16a.

Conclusions: 

The release of cyst fluid by rupture or leakage exposes remaining intact cysts to components that stimulate chloride secretion into the cyst lumen thus potentiating disease progression. This secretory activity is mediated by both CFTR and a calcium-activated chloride channel. This is the first demonstration of the involvement of calcium-activated chloride channels in the cellular response to ADPKD cyst fluid.