Regulation of aldose reductase and the polyol pathway activity by nitric oxide

Satish Srivastava, Kota Ramana, Deepak Chandra, Sanjay Srivastava, Aruni Bhatnagar

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Increased flux of glucose through the polyol pathway has been implicated in the pathophysiology of secondary diabetic complications. The first step of this pathway, which generates sorbitol from glucose, is catalyzed by aldose reductase (AR) (AKR1B). In vitro, the binding of substrates and inhibitors to AR is highly sensitive to the oxidation state of the enzyme due to the presence of a hyper-reactive cysteine residue at the active site of the enzyme. This residue (Cys-298) can be readily modified in air or, by thiol-modifying reagents, nitric oxide (NO) donors and nitrosothiols. We show that exposure of rat erythrocytes to NO donors inhibits AR activity and AR mediated accumulation of sorbitol, possibly by S-glutathiolation of Cys-298. Both glutathiolation and inhibition of AR are reversible upon subsequent incubation of the cells with fresh media without NO donors. These observations suggest that NO regulates the cellular activity of AR and in turn the flux of glucose via the polyol pathway. The inhibition of AR by exogenous or endogenous NO appears to be related to reversible S-glutathiolation of the AR protein. Because hyperglycemic states are associated with a decrease in NO generation, the loss of NO-mediated repression of AR may be a significant factor in the activation of the polyol pathway and the development of secondary diabetic complications.

Original languageEnglish (US)
Pages (from-to)333-340
Number of pages8
JournalChemico-Biological Interactions
Volume143-144
DOIs
StatePublished - Feb 1 2003

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Aldehyde Reductase
Nitric Oxide
Nitric Oxide Donors
Sorbitol
Diabetes Complications
Glucose
Fluxes
polyol
Sulfhydryl Reagents
Corrosion inhibitors
Enzymes
Sulfhydryl Compounds
Cysteine
Rats
Catalytic Domain
Erythrocytes
Chemical activation
Air
Cells
Oxidation

Keywords

  • Aldose reductase
  • In vivo
  • Nitric oxide
  • Polyol
  • SNAP
  • Sorbitol

ASJC Scopus subject areas

  • Toxicology

Cite this

Regulation of aldose reductase and the polyol pathway activity by nitric oxide. / Srivastava, Satish; Ramana, Kota; Chandra, Deepak; Srivastava, Sanjay; Bhatnagar, Aruni.

In: Chemico-Biological Interactions, Vol. 143-144, 01.02.2003, p. 333-340.

Research output: Contribution to journalArticle

Srivastava, Satish ; Ramana, Kota ; Chandra, Deepak ; Srivastava, Sanjay ; Bhatnagar, Aruni. / Regulation of aldose reductase and the polyol pathway activity by nitric oxide. In: Chemico-Biological Interactions. 2003 ; Vol. 143-144. pp. 333-340.
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