title: Pranlukast inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase.
abstract: Cysteinyl leukotriene receptor 1 (CysLT1 receptor) antagonists were found to inhibit chloride secretion in human airway epithelial cells. Since chloride secretion in renal epithelial cells, which shares common mechanisms with airway epithelial cells, plays important roles in renal cyst progression in polycystic kidney disease (PKD), this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms. Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney (MDCK) cyst models. Mechanisms of actions of CysLT1 receptor antagonists were determined using short-circuit current measurement, assays of cell viability and cell proliferation, and immunoblot analysis of signaling proteins. Of the three drugs acting as CysLT1 receptor antagonists (montelukast, pranlukast and zafirlukast) tested, pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability. Its effect was independent of the inhibition of CysLT1 receptors. Instead, it reduced cAMP-activated chloride secretion and proliferation of MDCK cells in an AMP-activated protein kinase (AMPK)-dependent manner and had no effect on CFTR protein expression. Interestingly, pranlukast enhanced AMPK activation via calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ) with consequent activation of acetyl-CoA carboxylase (ACC) and suppression of mammalian target of rapamycin (mTOR) pathway. These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting cAMP-activated chloride secretion and cell proliferation via CaMKKβ-AMPK-mTOR pathway. Therefore, pranlukast represents a class of known drugs that may have potential utility in PKD treatment.
authors.affiliation: Department of Physiology and Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Rama 6 Rd., Rajathevi, Bangkok 10400, Thailand.
authors.forename: Nutthapoom
authors.initials: N
authors.lastname: Pathomthongtaweechai
authors.affiliation: Department of Physiology and Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Rama 6 Rd., Rajathevi, Bangkok 10400, Thailand.
authors.forename: Sunhapas
authors.initials: S
authors.lastname: Soodvilai
authors.affiliation: Department of Physiology and Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Rama 6 Rd., Rajathevi, Bangkok 10400, Thailand.
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
authors.affiliation: Department of Physiology and Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Rama 6 Rd., Rajathevi, Bangkok 10400, Thailand. Electronic address: chatchai.mua@mahidol.ac.th.
authors.forename: Chatchai
authors.initials: C
authors.lastname: Muanprasat
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D003560:Cysts / Q000188:drug therapy / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000473:pathology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D061985:Madin Darby Canine Kidney Cells; D007690:Polycystic Kidney Diseases; D018077:Receptors, Leukotriene / Q000378:metabolism
chemical_list: D002712:Chlorides; D002867:Chromones; D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D055372:AMP-Activated Protein Kinases; C083169:leukotriene D4 receptor; C047681:pranlukast
keywords: AMPK; CFTR; Polycystic kidney disease; Pranlukast; mTOR