Critical role of TXNIP in oxidative stress, DNA damage and retinal pericyte apoptosis under high glucose: Implications for diabetic retinopathy

Takhellambam S. Devi, Ken Ichi Hosoya, Tetsuya Terasaki, Lalit P. Singh

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Diabetic retinopathy (DR) is characterized by early loss of retinal capillary pericytes and microvascular dysfunction. We recently showed that pro-oxidative stress and pro-apoptotic thioredoxin interacting protein (TXNIP) is significantly up-regulated in rat retinas in experimental diabetes and mediates inflammation and apoptosis. Therefore, we hypothesize here that TXNIP up-regulation in pericyte plays a causative role in oxidative stress and apoptosis under sustained high glucose exposure in culture. We maintained a rat retinal capillary pericyte cell line (TR-rPCT1) for 5 days under low glucose (LG, 5.5. mM) or high glucose (HG, 25. mM) with or without anti-oxidant N-acetylcysteine (5. mM, NAC), Azaseine (2. μM, AzaS), an inhibitor of TXNIP, and TXNIP siRNA (siTXNIP3, 20. nM). The results show that HG increases TXNIP expression in TR-rPCT1, which correlates positively with ROS generation, protein S-nitrosylation, and pro-apoptotic caspase-3 activation. Furthermore, pericyte apoptosis is demonstrated by DNA fragmentation (alkaline comet assay) and a reduction in MTT survival assay. Treatment of TR-rPCT1 with NAC or an inhibition of TXNIP by AzaS or siTXNIP3 each reduces HG-induced ROS, caspase-3 activation and DNA damage demonstrating that TXNIP up-regulation under chronic hyperglycemia is critically involved in cellular oxidative stress, DNA damage and retinal pericyte apoptosis. Thus, TXNIP represents a novel gene and drug target to prevent pericyte loss and progression of DR.

Original languageEnglish
Pages (from-to)1001-1012
Number of pages12
JournalExperimental Cell Research
Volume319
Issue number7
DOIs
Publication statusPublished - 2013 Apr 15

Keywords

  • Chromatin break
  • Diabetic retinopathy
  • Hyperglycemia
  • Mitochondrial dysfunction
  • Oxidative stress
  • Pericyte apoptosis
  • TXNIP

ASJC Scopus subject areas

  • Cell Biology

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