Activation of nuclear factor-kappaB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• The polyol pathway's role in diabetic complications is known, but molecular mechanisms are unclear.
• Hyperglycemia can activate inflammatory pathways, contributing to diabetic vascular disease.
• Aldose reductase is a key enzyme in the polyol pathway, catalyzing the first step.

Purpose of the Study:

• To investigate if inhibiting aldose reductase affects hyperglycemia-induced activation of nuclear factor-kappaB (NF-κB).
• To explore the role of protein kinase C (PKC) in this process.
• To assess the therapeutic potential of aldose reductase inhibition in diabetic vascular inflammation.

Main Methods:

• Vascular smooth muscle cells were treated with aldose reductase inhibitors (tolrestat, sorbinil) or PKC inhibitors.
• Aldose reductase was ablated using small interference RNA (siRNA).
• NF-κB activation, IKK phosphorylation, and inflammatory gene expression (ICAM-1, VCAM-1) were measured.
• Experiments included osmotic stimulation with mannitol and in vivo studies in diabetic rats.

Main Results:

• Aldose reductase inhibitors and siRNA prevented high-glucose-induced activation of NF-κB and AP-1.
• Inhibition of aldose reductase blocked PKC activation and subsequent NF-κB signaling.
• Tolrestat reduced activated NF-κB in diabetic rat carotid arteries.
• Mannitol stimulation activated NF-κB but not inflammatory adhesion molecules, and this was unaffected by aldose reductase inhibition.

Conclusions:

• Aldose reductase inhibition prevents PKC-dependent, non-osmotic NF-κB activation in response to hyperglycemia.
• This pathway is crucial for high-glucose-induced vascular inflammation.
• Targeting aldose reductase may be a viable strategy for managing diabetic vascular complications.