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 Scopus citations

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

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