Activation of nulcear factor-κB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase

Kota Ramana, Brian Friedrich, Sanjay Srivastava, Aruni Bhatnagar, Satish Srivastava

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Activation of the polyol pathway has been linked to the development of secondary diabetic complications. However, the underlying molecular mechanisms remain unclear. To probe the contribution of this pathway, we examined whether inhibition of aldose reductase, which catalyzes the first step of the pathway, affects hyperglycemia-induced activation of the inflammatory transcription factor nuclear factor (NF)-κB. Treatment of vascular smooth muscle cells with the aldose reductase inhibitors tolrestat and sorbinil prevented high-glucose-induced protein kinase C (PKC) activation, nuclear translocation of NF-κB, phosphorylation of IKK, and the increase in the expression of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and aldose reductase. High-glucose-induced NF-κB activation was also prevented by the PKC inhibitors chelerythrine and calphostin C. Ablation of aldose reductase by small interference RNA (siRNA) prevented high-glucose-induced NF-κB and AP-1 activation but did not affect the activity of SP-1 or OCT-1. Stimulation with iso-osmotic mannitol activated NF-κB and increased the expression of aldose reductase but not ICAM-1 and VCAM-1. Treatment with aldose reductase inhibitors or aldose reductase siRNA did not affect mannitol-induced NF-κB or AP-1 activation. Administration of tolrestat (15 mg · kg-1 · day-1) decreased the abundance of activated NF-κB in balloon-injured carotid arteries of diabetic rats. Collectively, these results suggest that inhibition of aldose reductase, which prevents PKC-dependent nonosmotic NF-κB activation, may be a useful approach for treating vascular inflammation caused by diabetes.

Original languageEnglish (US)
Pages (from-to)2910-2920
Number of pages11
JournalDiabetes
Volume53
Issue number11
DOIs
StatePublished - Nov 2004

Fingerprint

Aldehyde Reductase
Vascular Smooth Muscle
Hyperglycemia
Smooth Muscle Myocytes
Protein Kinase C
Vascular Cell Adhesion Molecule-1
Transcription Factor AP-1
Mannitol
RNA Interference
Glucose
Protein C Inhibitor
Diabetes Complications
Protein Kinase Inhibitors
Carotid Arteries
Blood Vessels
Transcription Factors
Phosphorylation
Inflammation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Activation of nulcear factor-κB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase. / Ramana, Kota; Friedrich, Brian; Srivastava, Sanjay; Bhatnagar, Aruni; Srivastava, Satish.

In: Diabetes, Vol. 53, No. 11, 11.2004, p. 2910-2920.

Research output: Contribution to journalArticle

Ramana, Kota ; Friedrich, Brian ; Srivastava, Sanjay ; Bhatnagar, Aruni ; Srivastava, Satish. / Activation of nulcear factor-κB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase. In: Diabetes. 2004 ; Vol. 53, No. 11. pp. 2910-2920.
@article{da34388795e140beb76162db2713e524,
title = "Activation of nulcear factor-κB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase",
abstract = "Activation of the polyol pathway has been linked to the development of secondary diabetic complications. However, the underlying molecular mechanisms remain unclear. To probe the contribution of this pathway, we examined whether inhibition of aldose reductase, which catalyzes the first step of the pathway, affects hyperglycemia-induced activation of the inflammatory transcription factor nuclear factor (NF)-κB. Treatment of vascular smooth muscle cells with the aldose reductase inhibitors tolrestat and sorbinil prevented high-glucose-induced protein kinase C (PKC) activation, nuclear translocation of NF-κB, phosphorylation of IKK, and the increase in the expression of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and aldose reductase. High-glucose-induced NF-κB activation was also prevented by the PKC inhibitors chelerythrine and calphostin C. Ablation of aldose reductase by small interference RNA (siRNA) prevented high-glucose-induced NF-κB and AP-1 activation but did not affect the activity of SP-1 or OCT-1. Stimulation with iso-osmotic mannitol activated NF-κB and increased the expression of aldose reductase but not ICAM-1 and VCAM-1. Treatment with aldose reductase inhibitors or aldose reductase siRNA did not affect mannitol-induced NF-κB or AP-1 activation. Administration of tolrestat (15 mg · kg-1 · day-1) decreased the abundance of activated NF-κB in balloon-injured carotid arteries of diabetic rats. Collectively, these results suggest that inhibition of aldose reductase, which prevents PKC-dependent nonosmotic NF-κB activation, may be a useful approach for treating vascular inflammation caused by diabetes.",
author = "Kota Ramana and Brian Friedrich and Sanjay Srivastava and Aruni Bhatnagar and Satish Srivastava",
year = "2004",
month = "11",
doi = "10.2337/diabetes.53.11.2910",
language = "English (US)",
volume = "53",
pages = "2910--2920",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "11",

}

TY - JOUR

T1 - Activation of nulcear factor-κB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase

AU - Ramana, Kota

AU - Friedrich, Brian

AU - Srivastava, Sanjay

AU - Bhatnagar, Aruni

AU - Srivastava, Satish

PY - 2004/11

Y1 - 2004/11

N2 - Activation of the polyol pathway has been linked to the development of secondary diabetic complications. However, the underlying molecular mechanisms remain unclear. To probe the contribution of this pathway, we examined whether inhibition of aldose reductase, which catalyzes the first step of the pathway, affects hyperglycemia-induced activation of the inflammatory transcription factor nuclear factor (NF)-κB. Treatment of vascular smooth muscle cells with the aldose reductase inhibitors tolrestat and sorbinil prevented high-glucose-induced protein kinase C (PKC) activation, nuclear translocation of NF-κB, phosphorylation of IKK, and the increase in the expression of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and aldose reductase. High-glucose-induced NF-κB activation was also prevented by the PKC inhibitors chelerythrine and calphostin C. Ablation of aldose reductase by small interference RNA (siRNA) prevented high-glucose-induced NF-κB and AP-1 activation but did not affect the activity of SP-1 or OCT-1. Stimulation with iso-osmotic mannitol activated NF-κB and increased the expression of aldose reductase but not ICAM-1 and VCAM-1. Treatment with aldose reductase inhibitors or aldose reductase siRNA did not affect mannitol-induced NF-κB or AP-1 activation. Administration of tolrestat (15 mg · kg-1 · day-1) decreased the abundance of activated NF-κB in balloon-injured carotid arteries of diabetic rats. Collectively, these results suggest that inhibition of aldose reductase, which prevents PKC-dependent nonosmotic NF-κB activation, may be a useful approach for treating vascular inflammation caused by diabetes.

AB - Activation of the polyol pathway has been linked to the development of secondary diabetic complications. However, the underlying molecular mechanisms remain unclear. To probe the contribution of this pathway, we examined whether inhibition of aldose reductase, which catalyzes the first step of the pathway, affects hyperglycemia-induced activation of the inflammatory transcription factor nuclear factor (NF)-κB. Treatment of vascular smooth muscle cells with the aldose reductase inhibitors tolrestat and sorbinil prevented high-glucose-induced protein kinase C (PKC) activation, nuclear translocation of NF-κB, phosphorylation of IKK, and the increase in the expression of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and aldose reductase. High-glucose-induced NF-κB activation was also prevented by the PKC inhibitors chelerythrine and calphostin C. Ablation of aldose reductase by small interference RNA (siRNA) prevented high-glucose-induced NF-κB and AP-1 activation but did not affect the activity of SP-1 or OCT-1. Stimulation with iso-osmotic mannitol activated NF-κB and increased the expression of aldose reductase but not ICAM-1 and VCAM-1. Treatment with aldose reductase inhibitors or aldose reductase siRNA did not affect mannitol-induced NF-κB or AP-1 activation. Administration of tolrestat (15 mg · kg-1 · day-1) decreased the abundance of activated NF-κB in balloon-injured carotid arteries of diabetic rats. Collectively, these results suggest that inhibition of aldose reductase, which prevents PKC-dependent nonosmotic NF-κB activation, may be a useful approach for treating vascular inflammation caused by diabetes.

UR - http://www.scopus.com/inward/record.url?scp=7044247670&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=7044247670&partnerID=8YFLogxK

U2 - 10.2337/diabetes.53.11.2910

DO - 10.2337/diabetes.53.11.2910

M3 - Article

VL - 53

SP - 2910

EP - 2920

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 11

ER -