IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose

The activated insulin-like growth factor-1 receptor (IGF-1R) protects cells from a wide range of apoptotic stimuli. Hyperglycemia promotes the intracellular generation of superoxide anion and hydrogen peroxide, both of which have been linked to the activation of the mitochondrial apoptosis program....

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Bibliographic Details
Published in:American journal of physiology. Renal physiology 2003-11, Vol.285 (5), p.F1013-F1024
Main Authors: Kang, Barinder P S, Urbonas, Arunas, Baddoo, Andrew, Baskin, Stuart, Malhotra, Ashwani, Meggs, Leonard G
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Butadienes - pharmacology
Cell Survival - drug effects
Cell Survival - physiology
Cells, Cultured
Chromones - pharmacology
Cytochromes c - metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Glomerular Mesangium - cytology
Glomerular Mesangium - drug effects
Glomerular Mesangium - physiology
Glucose - administration & dosage
Humans
Insulin-Like Growth Factor I - pharmacology
Membrane Potentials - physiology
Mice
Mitochondria - metabolism
Mitochondria - physiology
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - metabolism
Morpholines - pharmacology
Nitriles - pharmacology
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphorylation
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-bcl-2 - metabolism
Reactive Oxygen Species - antagonists & inhibitors
Receptor, IGF Type 1 - physiology
Tumor Suppressor Protein p53 - metabolism
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Summary:The activated insulin-like growth factor-1 receptor (IGF-1R) protects cells from a wide range of apoptotic stimuli. Hyperglycemia promotes the intracellular generation of superoxide anion and hydrogen peroxide, both of which have been linked to the activation of the mitochondrial apoptosis program. Here, we report for the first time that ligand activation of the IGF-1R protects normal human mesangial cells and SV40 murine mesangial cells from the glycol-oxidant-induced apoptosis program. The IGF-1R antiapoptosis program was dependent on the recruitment of both Akt/PKB and the ERK subfamily of mitogen-activated protein kinases. IGF-1 treatment also protected the redox potential of mesangial cells maintained at high ambient glucose concentration, by inhibiting the generation of reactive oxygen intermediates and preserving mitochondrial transmembrane potential. IGF-1R survival signals targeted the Bcl-2 family of proteins to protect against glucose-induced apoptosis and oxidative stress. IGF-1-treated cells exhibited a decrease in the Bax/Bcl-2 ratio; increased phosphorylation/inactivation of Bad at Ser112 and Ser136; inhibition of cytochrome c release; perturbations directionally opposed to the initiation of the apoptosis program. In addition, we demonstrate IGF-1R-activated ERK signaling modules phosphorylate Ser112 of the mitochondrial Bad protein, establishing a direct link between surface IGF-1R and the survival program in mitochondria. Our findings indicate that in mesangial cells maintained at high ambient glucose concentration, IGF-1 activates a survival program that maintains the integrity of mitochondria and prevents the expression of the genetic program for apoptosis.
ISSN:1931-857X
1522-1466
DOI:10.1152/ajprenal.00209.2003