ABSTRACT
BACKGROUND: Renal bilateral fluid filled-cyst in polycystic kidney disease (PKD) is associated with abnormal epithelial cell proliferation and transepithelial fluid secretion which leads to end-stage renal disease (ESRD). A chalcone derivative, isoliquiritigenin (ISLQ), has been shown to have various pharmacological properties. Since several studies have shown that ISLQ could inhibit CFTR channel activity, it is interesting to see whether it can inhibit renal cyst enlargement. The present study was aimed to determine an inhibitory effect and the mechanism of chalcone derivatives on MDCK cyst progression and Pkd1 mutant cells. METHODS: MDCK cyst growth and cyst formation experiments, MTT assay, Ussing chamber experiment, BrdU cell proliferation assay and western blot analysis were performed in this study. RESULTS: Among four compounds of chalcone derivatives tested, CHAL-005 (100 µM) was found to inhibit MDCK cyst growth in a dose-dependent manner without cytotoxicity. It inhibited short-circuit current of chloride secretion as well as CFTR protein expression in MDCK cells. CHAL-005 significantly suppressed cell proliferation. In addition, CHAL-005 strongly reduced phosphorylation ERK1/2 and phosphorylation S6 kinase in MDCK and Pkd1 mutant cells. Interestingly, CHAL-005 activated phosphorylation of AMP kinase protein expression in MDCK and Pkd1 mutant cells. CONCLUSION: CHAL-005 slowed MDCK cyst progression by inhibiting CFTR expression and reducing ERK1/2 and mTOR/S6K signaling pathways as well as activating AMPK expression. Therefore, a chalcone derivative could represent as a promising drug candidate for polycystic kidney disease intervention.
Subject(s)
Cell Proliferation/drug effects , Chalcones/pharmacology , Cyst Fluid/drug effects , Cyst Fluid/metabolism , Enzyme Inhibitors/pharmacology , AMP-Activated Protein Kinases/metabolism , Animals , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Dogs , MAP Kinase Signaling System/drug effects , Madin Darby Canine Kidney Cells , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mutation , Phosphorylation/drug effects , Polycystic Kidney Diseases/drug therapy , Ribosomal Protein S6 Kinases/metabolism , TRPP Cation Channels/geneticsABSTRACT
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 (50â¯mg/kgBW) for 4â¯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.
Subject(s)
Cell Proliferation/drug effects , Cyst Fluid/drug effects , Cyst Fluid/metabolism , Lansoprazole/therapeutic use , Polycystic Kidney Diseases/drug therapy , Polycystic Kidney Diseases/metabolism , Animals , Cell Proliferation/physiology , Dogs , Dose-Response Relationship, Drug , Humans , Lansoprazole/pharmacology , Madin Darby Canine Kidney Cells , Male , Polycystic Kidney Diseases/pathology , Proton Pump Inhibitors/pharmacology , Proton Pump Inhibitors/therapeutic use , Rats , Rats, TransgenicSubject(s)
Anthelmintics/pharmacology , Cysts/chemistry , Echinococcus/physiology , Gerbillinae/parasitology , Glucose/analysis , Glycogen/analysis , Guanidines/pharmacology , Animals , Cyst Fluid/chemistry , Cyst Fluid/drug effects , Cysts/parasitology , Cysts/pathology , Drug Administration Schedule , Echinococcus/drug effects , Glucose/metabolism , Glycogen/metabolismABSTRACT
Gross cystic breast disease (GCBD) is common in women, especially in the age range between 35 and the menopausal years. The present study examined the possible role of progesterone (Pg) in the chorionic gonadotropin (hCG) concentration in GCBD. The breast cyst fluids (BCFs) were drawn by fine needle aspiration between the sixth and the eighth day of the menstrual cycle and twenty days later. On the day of the first aspiration the patient began to take 100 mg of natural micronized Pg orally until the second aspiration. At both times blood samples were also taken. Determinations were done of both BCFs and blood sample using two fully automated chemiluminiscent enzyme immunometric assays. Pg has been demonstrated to induce a significant increment in hCG + free ss-hCG (median, range): 0.27 ng/ml, 0.12-6.24 vs. 1.92 ng/ml, 0.12-423.5; free ss-hCG: 0.11 ng/ml, 0.02-2.40 vs. 0.91 ng/ml, 0.02-58.40 in the BCFs, with no change in the circulating concentrations of the hormone. None of the sera studied presented levels of hCG + free ss-hCG or free ss-hCG above 0.5 ng/ml or 0.1 ng/ml, respectively. The occurrence of hCG or a derivative polypeptide in BCFs, when they are present in high concentrations suggests that this glycoprotein could be synthesized in situ and possibly involved in the pathogenesis of GCBD by the degree of differentiation of breast epithelial cells induced by the hormone.
