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IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose
Barinder P S Kang1, Arunas Urbonas, Andrew Baddoo
1Division of Nephrology, Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA.
Abstract:
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.
Insights
Insulin-like growth factor-1 receptor (IGF-1R) activation protects kidney mesangial cells from high glucose-induced apoptosis. This survival pathway involves Akt/PKB and ERK signaling, preserving mitochondrial function and inhibiting cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Renal Physiology
Background:
- Hyperglycemia induces oxidative stress and mitochondrial apoptosis.
- Insulin-like growth factor-1 receptor (IGF-1R) signaling is crucial for cell survival.
Purpose of the Study:
- To investigate the protective role of IGF-1R activation against hyperglycemia-induced apoptosis in mesangial cells.
- To elucidate the signaling pathways involved in IGF-1R-mediated cytoprotection.
Main Methods:
- Ligand activation of IGF-1R in human and murine mesangial cells.
- Assessment of apoptosis, reactive oxygen species generation, and mitochondrial potential.
- Analysis of key apoptosis regulatory proteins (Bcl-2 family) and kinase activity (Akt/PKB, ERK).
Main Results:
- IGF-1R activation protected mesangial cells from glycol-oxidant-induced apoptosis.
- The protective effect was dependent on Akt/PKB and ERK signaling.
- IGF-1 treatment preserved mitochondrial function and inhibited apoptosis by modulating Bcl-2 family proteins, including Bad phosphorylation.
- ERK signaling directly phosphorylated mitochondrial Bad, linking surface IGF-1R to mitochondrial survival.
Conclusions:
- IGF-1R activation initiates a survival program in mesangial cells under high glucose conditions.
- This program involves Akt/PKB and ERK pathways, leading to mitochondrial protection and inhibition of apoptosis.
- IGF-1R signaling represents a potential therapeutic target for diabetic nephropathy complications.