Parathyroid hormone(1-34)-induced apoptosis in neuronal rat PC12 cells: Implications for neurotoxicity

• Published in: Pathology, research and practice research and practice, 2010-12, Vol.206 (12), p.821-827
• Main Authors: An, Hui-Xia, Jin, Zhan-Feng, Ge, Xiao-Feng, Wu, Jing, Chen, Chang, Zhang, Feng-Min, Qu, Wei, Liu, Xiao-Gang, Liu, Su-Yan
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Blotting, Western; Caspase 3 - metabolism; Cell Death - drug effects; Cell Survival; Cytochromes c - metabolism; Cytochromes c - secretion; Cytotoxicity; DNA Fragmentation; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; Flavonoids - antagonists & inhibitors; Flow Cytometry; Imidazoles - antagonists & inhibitors; L-Lactate Dehydrogenase - metabolism; Mitochondria - metabolism; p38; p38 Mitogen-Activated Protein Kinases - metabolism; Parathyroid Hormone - adverse effects; Parathyroid Hormone - metabolism; Parathyroid Hormone - pharmacology; Parathyroid hormone(1-34); PC12 cell; PC12 Cells; Pyridines - antagonists & inhibitors; Rats; Signal Transduction; Time Factors; Up-Regulation
• ISSN: 0344-0338; 1618-0631
• DOI: 10.1016/j.prp.2010.09.006

Based on accumulated evidence, we speculate that a high concentration of parathyroid hormone (PTH) may cause neurotoxicity in patients with uremia through apoptosis-induced neuropathy. In this study, we demonstrated that in vitro stimulation with PTH(1-34) induced a significant decrease in PC12 cell numbers in both dosage- and time-dependent fashions when these cells were treated with PTH(1-34) at concentrations of 0.01, 0.1 or 1.0 μM for 24, 48, 72, and 96 h, respectively, as assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Decreased numbers of PC12 cells were caused by PTH(1-34)-induced apoptotic and cytotoxic processes, as determined by DNA fragmentation, flow cytometry, and lactate dehydrogenase (LDH)-leakage assays. Upregulation of the extracellular signal-regulated kinase (ERK) and p38 signaling pathway was the underlying mechanism responsible for 1.0 μM PTH(1-34)-induced apoptosis in PC12 cells, as elucidated by Western blotting analysis and confirmed with ERK and p38 inhibitors. Furthermore, 1.0 μM PTH(1-34)-induced apoptosis was accompanied by a release of cytochrome c and subsequent caspase-3 activation. These data suggest that a high concentration of PTH(1-34)-induced cytotoxicity and apoptosis in PC12 cells was associated with upregulation of ERK and p38 through a mitochondria-mediated apoptotic pathway.