Human cyst fluid from autosomal dominant polycystic kidney disease (ADPKD) patients stimulates two interacting chloride channels

Abstract

In ADPKD renal cysts enlarge slowly over a patient's lifetime, but renal function remains intact until midlife. Once renal function begins to decline, renal failure occurs rapidly. Studies were performed to determine the factors that may be involved in the cyst expansion and renal decline during the last stage of ADPKD. We used electrophysiology techniques to study ion transport of a mouse principal cells of the cortical collecting duct (mpkCCD) cell line after exposure to human cyst fluid. It was previously shown that basolateral addition of cyst fluid stimulated a Cl− secretory response and that the active component of cyst fluid is lysophosphatidic acid (LPA). Inhibitor studies indicate that the Clsecretory response is due to activation of the cystic fibrosis transmembrane conductance regulator (CFTR) as well as a Ca2+‐ activated Cl− channel (CaCC), with the characteristics of TMEM16A. Interestingly, the LPA stimulated Cl− secretory response is not accompanied by increased cAMP and is substantially inhibited by Bapta‐AM, a chelator of intracellular Ca2+. These results suggest a key role for Ca2+ in the LPA‐stimulated Cl− secretory response as well as an interaction between CFTR and CaCC.