Autosomal dominant polycystic kidney disease is characterized by innumerous fluid-filled kidney cysts. Net fluid secretion into renal cysts is driven by transepithelial Cl- secretion mediated by apical cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels and is an important factor in kidney enlargement.
We have found that the K+ channel KCa3.1 plays a critical role in the regulation of CFTR-mediated Cl- secretion in epithelial cells derived from the cysts of ADPKD kidneys. We found that forskolin, a potent adenylyl cyclase agonist, stimulated anion secretion by ADPKD cell monolayers and that TRAM-34, a specific KCa3.1 blocker, inhibited this Cl- current. TRAM-34 also inhibited in vitro cyst formation and enlargement by cells cultured within a collagen gel.
Taken together, these data suggest that KCa3.1 channels play a critical role in transcellular Cl- secretion and net fluid transport into the cysts of ADPKD kidneys, by maintaining the electrochemical driving force for Cl- efflux through apical Cl channels.
We propose that pharmacological inhibitors of KCa3.1 channels may provide a novel and effective therapy to delay progression to kidney failure in patients with ADPKD and are currently testing this in animal models of ADPKD.