title: TRPC6 channel activation promotes neonatal glomerular mesangial cell apoptosis via calcineurin/NFAT and FasL/Fas signaling pathways.
abstract: Glomerular mesangial cell (GMC) proliferation and death are involved in the pathogenesis of glomerular disorders. The mechanisms that control GMC survival are poorly understood, but may include signal transduction pathways that are modulated by changes in intracellular Ca(2+) ([Ca(2+)]i) concentration. In this study, we investigated whether activation of the canonical transient receptor potential (TRPC) 6 channels and successive [Ca(2+)]i elevation alter neonatal GMC survival. Hyperforin (HF)-induced TRPC6 channel activation increased [Ca(2+)]i concentration, inhibited proliferation, and triggered apoptotic cell death in primary neonatal pig GMCs. HF-induced neonatal GMC apoptosis was not associated with oxidative stress. However, HF-induced TRPC6 channel activation stimulated nuclear translocation of the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). HF also increased cell death surface receptor Fas ligand (FasL) level and caspase-8 activity in the cells; effects mitigated by [Ca(2+)]i chelator BAPTA, calcineurin/NFAT inhibitor VIVIT, and TRPC6 channel knockdown. Accordingly, HF-induced neonatal GMC apoptosis was attenuated by BAPTA, VIVIT, Fas blocking antibody, and a caspase-3/7 inhibitor. These findings suggest that TRPC6 channel-dependent [Ca(2+)]i elevation and the ensuing induction of the calcineurin/NFAT, FasL/Fas, and caspase signaling cascades promote neonatal pig GMC apoptosis.
authors.affiliation: Department of Physiology University of Tennessee Health Science Center, Memphis TN, USA.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Soni
authors.affiliation: Department of Physiology University of Tennessee Health Science Center, Memphis TN, USA.
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adebiyi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019703:Calcineurin / Q000502:physiology*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D053181:Caspase 8 / Q000502:physiology; D061945:Caspase Inhibitors / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000502:physiology*; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D034421:Sus scrofa; D000074287:TRPC6 Cation Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013729:Terpenes / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology*
chemical_list: D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; D009842:Oligopeptides; D034741:RNA, Small Interfering; D000074287:TRPC6 Cation Channel; D013729:Terpenes; C121611:VIVIT peptide; D019014:fas Receptor; D004533:Egtazic Acid; D010696:Phloroglucinol; D019703:Calcineurin; D053181:Caspase 8; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C001654:hyperforin; D002118:Calcium