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

Abstract

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.

• Authors: Hui-Xia An, Zhan-Feng Jin, Xiao-Feng Ge, Jing Wu, Chang Chen, Feng-Min Zhang, Wei Qu, Xiao-Gang Liu, Su-Yan Liu
• Journal: Pathology, research and practice (Pathol Res Pract) Vol. 206 Issue 12 Pg. 821-7 (Dec 15 2010) ISSN: 1618-0631 [Electronic] Germany
• PMID: 20971569 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier GmbH. All rights reserved.

Chemical References

• Flavonoids
• Imidazoles
• Parathyroid Hormone
• Pyridines
• Cytochromes c
• L-Lactate Dehydrogenase
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Casp3 protein, rat
• Caspase 3
• SB 203580
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 3 (metabolism)
• Cell Death (drug effects)
• Cell Survival
• Cytochromes c (metabolism)
• DNA Fragmentation
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Flavonoids (antagonists & inhibitors)
• Flow Cytometry
• Imidazoles (antagonists & inhibitors)
• L-Lactate Dehydrogenase (metabolism)
• Mitochondria (metabolism)
• PC12 Cells
• Parathyroid Hormone (adverse effects, metabolism, pharmacology)
• Pyridines (antagonists & inhibitors)
• Rats
• Signal Transduction
• Time Factors
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)