Lansoprazole reduces renal cyst in polycystic kidney disease via inhibition of cell proliferation and fluid secretion.

Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) is mediated by abnormal cyst-ling cell proliferation and fluid accumulation. Liver X receptor (LXR)-activating ligands suppresses renal cyst enlargement by modulation of cysticfibrosis transmembrane conductance regulator (CFTR)-mediated fluid accumulation. Lansoprazole has been reported as agonist of LXR, and shows an anti-proliferative effect in cancer cells. Here, lansoprazole's pharmacological effect and underlying mechanism on renal cyst development and expansion in in vitro; human ADPKD cyst-lining epithelial cell line and Type I Mardin Darby Canine Kidney (MDCK) cells, and in vivo models was investigated. Lansoprazole inhibited cyst development via inhibition of cell proliferation. In renal cells, lansoprazole's anti-proliferative effect was mediated by inhibition of mTOR/S6K and extracellular signal-regulated kinase (ERK) signaling proteins. In addition, lansoprazole inhibited CFTR-mediated fluid secretion via reduction of CFTR protein expression. In PCK rats, administering lansoprazole (50 mg/kgBW) for 4 weeks produced significant decreases in the cystic area and improved renal function by reduction of plasma creatinine and blood urea nitrogen. Inhibition of mTOR/S6K, ERK, and CFTR protein expression was observed in PCK rat kidney following lansoprazole treatment. The findings point to potential therapeutic application of lansoprazole in ADPKD.

Renal organic cation transporters mediated cadmium-induced nephrotoxicity.

The involvement of renal organic cation transporters (OCTs) in cadmium transport was investigated in Chinese hamster ovary (CHO-K1) cells stably and singly transfected with rabbit (rb)OCT1 and rbOCT2, in murine isolated renal proximal tubule, and in intact kidney following bilateral ureteral ligation of rat. Cadmium inhibited uptake of [(3)H]-tetraethylammonium (TEA), a substrate of rbOCT1 and rbOCT2, via both transporters with half maximal inhibitory concentration (IC(50)) of cadmium for rbOCT1- and rbOCT2-mediated TEA uptake of 96±5µM and 207±12µM, respectively. Cadmium similarly inhibited [(3)H]-TEA uptake in isolated non perfused renal proximal tubules. Cadmium accumulation in the transfected CHO-K1 cells was significantly higher than that of parent cells and this could be attenuated by TEA. In addition, cadmium accumulation in whole kidney was also reduced by TEA administration. Furthermore, exposure of the rbOCT1- and rbOCT2-expressing CHO-K1 cells to cadmium led to cytotoxicity, which could be prevented by TEA treatment. Taken together, this study provides for the first time, evidence showing OCT1 and OCT2 mediating cadmium transport across the basolateral membrane into the renal proximal tubular cells.