Metabolites of lansoprazole inhibit CFTR-mediated Cl–transport and retard cyst progression

Abstract

Polycystic kidney disease (PKD) is a genetic disorder that results in renal cyst formation and cyst enlargement. PKD causes abnormal cell proliferation and fluid secretion in the cyst which results in a loss of normal function and eventually leads to renal failure. A previous study reported the beneficial effect of lansoprazole, a proton pump inhibitor, on cyst progression in vitro and renal cyst progression in PKD rats. The present study investigated whether the major metabolites of lansoprazole, lansoprazole sulfide, and lansoprazole sulfone affected the progression of microcysts derived from the Madin Darby canine kidney (MDCK) cells. The results showed that treatment of the MDCK cells with lansoprazole sulfide or lansoprazole sulfone increased the expression of sterol regulatory element-binding protein-1c (SREBP-1c), a target protein of the liver X receptor. Lansoprazole sulfide or lansoprazole sulfone significantly inhibited cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl^– secretion compared with vehicle-treating cells. However, they did not affect calcium-activated chloride channel (CaCC)-mediated Cl^–secretion. Incubation of MDCK-derived cysts with lansoprazole sulfide or lansoprazole sulfone for 3 and 6 days led to a decrease in the growth of the cysts without affecting the viability of the cells. In addition, lansoprazole sulfide significantly reduced the number of forskolin-induced cysts, but lansoprazole sulfone had no effect. The inhibitory effect of lansoprazole sulfide on cyst formation was related to reduced cell proliferation. This finding is the first in vitro evidence supporting that the metabolites of lansoprazole could inhibit Cl^– secretion and suppress cyst progression of the renal collecting duct cells.