title: Naproxen-induced Ca2+ movement and death in MDCK canine renal tubular cells.
abstract: Naproxen is an anti-inflammatory drug that affects cellular calcium ion (Ca(2+)) homeostasis and viability in different cells. This study explored the effect of naproxen on [Ca(2+)](i) and viability in Madin-Darby canine kidney cells (MDCK) canine renal tubular cells. At concentrations between 50 μM and 300 μM, naproxen induced [Ca(2+)](i) rises in a concentration-dependent manner. This Ca(2+) signal was reduced partly when extracellular Ca(2+) was removed. The Ca(2+) signal was inhibited by a Ca(2+) channel blocker nifedipine but not by store-operated Ca(2+) channel inhibitors (econazole and SKF96365), a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate, and a PKC inhibitor GF109203X. In Ca(2+)-free medium, pretreatment with 2,5-di-tert-butylhydroquinone or thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+) pumps, partly inhibited naproxen-induced Ca(2+) signal. Inhibition of phospholipase C with U73122 did not alter naproxen-evoked [Ca(2+)](i) rises. At concentrations between 15 μM and 30 μM, naproxen killed cells in a concentration-dependent manner, which was not reversed by prechelating cytosolic Ca(2+) with the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl. Annexin V/propidium iodide staining data suggest that naproxen induced apoptosis. Together, in MDCK renal tubular cells, naproxen induced [Ca(2+)](i) rises by inducing Ca(2+) release from multiple stores that included the endoplasmic reticulum and Ca(2+) entry via nifedipine-sensitive Ca(2+) channels. Naproxen induced cell death that involved apoptosis.
authors: Department of Medicine, Chang Bing Show Chwan Memorial Hospital, Changhua County, Taiwan.
authors: H-H
authors: HH
authors: Cheng
authors: Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Chia-Yi, Taiwan Chronic Diseases and Health Promotion Research Center, Chang Gung Institute of Technology, Chia-Yi, Taiwan.
authors: C-T
authors: CT
authors: Chou
authors: Division of Pediatrics, St. Joseph Hospital, Kaohsiung, Taiwan.
authors: T-K
authors: TK
authors: Sun
authors: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors: W-Z
authors: WZ
authors: Liang
authors: Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors: J-S
authors: JS
authors: Cheng
authors: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors: H-T
authors: HT
authors: Chang
authors: Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors: H-W
authors: HW
authors: Tseng
authors: Department of Nursing, Tzu Hui Institute of Technology, Pingtung, Taiwan.
authors: C-C
authors: CC
authors: Kuo
authors: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors: F-A
authors: FA
authors: Chen
authors: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors: D-H
authors: DH
authors: Kuo
authors: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors: P
authors: P
authors: Shieh
authors: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan crjan@isca.vghks.gov.tw.
authors: C-R
authors: CR
authors: Jan
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004285:Dogs; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects* / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D009288:Naproxen / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D009288:Naproxen; D011493:Protein Kinase C; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium
keywords: Apoptosis; Ca2+; MDCK; endoplasmic reticulum; naproxen; nifedipine