The pathogenesis of diabetic complications

The role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

Levente Kiss, Csaba Szabo

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Recent work has demonstrated that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain triggers several pathways of injury [(protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product formation (AGE)] involved in the pathogenesis of diabetic complications by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. On the other hand, PARP activation results in inhibition of GAPDH by poly-ADP-ribosylation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC and AGE formation are prevented by inhibition of PARP activity. Furthermore, inhibition of PARPprotects against diabetic cardiovascular dysfunction in rodent models of cardiomyopathy, nephropathy, neuropathy, and retinopathy. PARP activation is also present in microvasculature of human diabetic subjects. The present review focuses on the role ofPARP in diabetic complications and emphasizes the therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.

Original languageEnglish (US)
Pages (from-to)29-37
Number of pages9
JournalMemorias do Instituto Oswaldo Cruz
Volume100
Issue numberSUPPL. 1
StatePublished - 2005
Externally publishedYes

Fingerprint

Peroxynitrous Acid
Poly(ADP-ribose) Polymerases
Diabetes Complications
Cytotoxicity
DNA Damage
Chemical activation
DNA
Glyceraldehyde-3-Phosphate Dehydrogenases
Electron Transport
Hyperglycemia
Protein Kinase C
Hexosamines
Advanced Glycosylation End Products
Blood vessels
Glycolysis
Microvessels
Cardiomyopathies
Superoxides
NAD
Adenosine Diphosphate

Keywords

  • Diabetic complications
  • Endothelial dysfunction
  • Nitric oxide
  • Oxidative stress
  • Peroxynitrite
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology
  • Immunology
  • Microbiology (medical)
  • Clinical Biochemistry

Cite this

@article{47edc36564f644518ddc87c8dbcc9b78,
title = "The pathogenesis of diabetic complications: The role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity",
abstract = "Recent work has demonstrated that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain triggers several pathways of injury [(protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product formation (AGE)] involved in the pathogenesis of diabetic complications by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. On the other hand, PARP activation results in inhibition of GAPDH by poly-ADP-ribosylation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC and AGE formation are prevented by inhibition of PARP activity. Furthermore, inhibition of PARPprotects against diabetic cardiovascular dysfunction in rodent models of cardiomyopathy, nephropathy, neuropathy, and retinopathy. PARP activation is also present in microvasculature of human diabetic subjects. The present review focuses on the role ofPARP in diabetic complications and emphasizes the therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.",
keywords = "Diabetic complications, Endothelial dysfunction, Nitric oxide, Oxidative stress, Peroxynitrite, Poly(ADP-ribose) polymerase",
author = "Levente Kiss and Csaba Szabo",
year = "2005",
language = "English (US)",
volume = "100",
pages = "29--37",
journal = "Memorias do Instituto Oswaldo Cruz",
issn = "0074-0276",
publisher = "Fundacao Oswaldo Cruz",
number = "SUPPL. 1",

}

TY - JOUR

T1 - The pathogenesis of diabetic complications

T2 - The role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

AU - Kiss, Levente

AU - Szabo, Csaba

PY - 2005

Y1 - 2005

N2 - Recent work has demonstrated that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain triggers several pathways of injury [(protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product formation (AGE)] involved in the pathogenesis of diabetic complications by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. On the other hand, PARP activation results in inhibition of GAPDH by poly-ADP-ribosylation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC and AGE formation are prevented by inhibition of PARP activity. Furthermore, inhibition of PARPprotects against diabetic cardiovascular dysfunction in rodent models of cardiomyopathy, nephropathy, neuropathy, and retinopathy. PARP activation is also present in microvasculature of human diabetic subjects. The present review focuses on the role ofPARP in diabetic complications and emphasizes the therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.

AB - Recent work has demonstrated that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain triggers several pathways of injury [(protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product formation (AGE)] involved in the pathogenesis of diabetic complications by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. On the other hand, PARP activation results in inhibition of GAPDH by poly-ADP-ribosylation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC and AGE formation are prevented by inhibition of PARP activity. Furthermore, inhibition of PARPprotects against diabetic cardiovascular dysfunction in rodent models of cardiomyopathy, nephropathy, neuropathy, and retinopathy. PARP activation is also present in microvasculature of human diabetic subjects. The present review focuses on the role ofPARP in diabetic complications and emphasizes the therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.

KW - Diabetic complications

KW - Endothelial dysfunction

KW - Nitric oxide

KW - Oxidative stress

KW - Peroxynitrite

KW - Poly(ADP-ribose) polymerase

UR - http://www.scopus.com/inward/record.url?scp=18844395611&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18844395611&partnerID=8YFLogxK

M3 - Article

VL - 100

SP - 29

EP - 37

JO - Memorias do Instituto Oswaldo Cruz

JF - Memorias do Instituto Oswaldo Cruz

SN - 0074-0276

IS - SUPPL. 1

ER -