title: Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells.
abstract: We used mouse cortical collecting duct principal cells (mpkCCDc14 cell line) as a model to determine whether statins reduce the harmful effects of cyclosporine A (CsA) on the distal nephron. The data showed that treatment of cells with CsA increased transepithelial resistance and that the effect of CsA was abolished by lovastatin. Scanning ion conductance microscopy showed that CsA significantly increased the height of cellular protrusions near tight junctions. In contrast, lovastatin eliminated the protrusions and even caused a modest depression between cells. Western blot analysis and confocal microscopy showed that lovastatin also abolished CsA-induced elevation of both zonula occludens-1 and cholesterol in tight junctions. In contrast, a high concentration of CsA induced apoptosis, which was also attenuated by lovastatin, elevated intracellular ROS via activation of NADPH oxidase, and increased the expression of p47phox. Sustained treatment of cells with lovastatin also induced significant apoptosis, which was attenuated by CsA, but did not elevate intracellular ROS. These results indicate that both CsA and lovastatin are harmful to principal cells of the distal tubule, but via ROS-dependent and ROS-independent apoptotic pathways, respectively, and that they counteract probably via mobilization of cellular cholesterol levels.
authors.affiliation: Department of Cardiology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Bing-Chen
authors.initials: BC
authors.lastname: Liu
authors.forename: Xiang
authors.initials: X
authors.lastname: Song
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Lu
authors.forename: Charles Z
authors.initials: CZ
authors.lastname: Fang
authors.forename: Shi-Peng
authors.initials: SP
authors.lastname: Wei
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Alli
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Eaton
authors.forename: Bao-Zhong
authors.initials: BZ
authors.lastname: Shen
authors.forename: Xue-Qi
authors.initials: XQ
authors.lastname: Li
authors.forename: He-Ping
authors.initials: HP
authors.lastname: Ma
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D004396:Coloring Agents; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000648:ultrastructure; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007685:Kidney Tubules, Collecting / Q000166:cytology* / Q000187:drug effects* / Q000648:ultrastructure; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D019255:NADPH Oxidases / Q000378:metabolism; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis
chemical_list: D004396:Coloring Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D062826:Zonula Occludens-1 Protein; D016572:Cyclosporine; D002784:Cholesterol; D008148:Lovastatin; D019255:NADPH Oxidases
keywords: cholesterol; confocal microscopy; kidney injury; reactive oxygen species; scanning ion conductance microscopy; transepithelial resistance; zonula occludens-1