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

被引:9
作者
Nantavishit, Jiriporn [1 ,2 ]
Chatsudthipong, Varanuj [1 ]
Soodvilai, Sunhapas [1 ,3 ]
机构
[1] Mahidol Univ, Fac Sci, Dept Physiol, Res Ctr Transport Prot Med Innovat, Rama VI Rd, Bangkok 10400, Thailand
[2] Mahidol Univ, Fac Sci, Toxicol Grad Program, Rama VI Rd, Bangkok 10400, Thailand
[3] Mahidol Univ, Excellent Ctr Drug Discovery, Rama VI Rd, Bangkok 10400, Thailand
关键词
Polycystic kidney disease; Fluid secretion; Liver X receptor; mTOR; Extracellular signal-regulated kinases; CFTR; PROTON PUMP INHIBITORS; LIVER X RECEPTORS; AUTOSOMAL-DOMINANT; TOLVAPTAN; KINASE; MODEL; CYSTOGENESIS; PROGRESSION; ACTIVATION; MECHANISMS;
D O I
10.1016/j.bcp.2018.05.005
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:175 / 182
页数:8
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