Aldose reductase regulates high glucose-induced ectodomain shedding of tumor necrosis factor (TNF)-α via protein kinase C-δ and TNF-α converting enzyme in vascular smooth muscle cells

Aramati B.M. Reddy, Kota V. Ramana, Sanjay Srivastava, Aruni Bhatnagar, Satish K. Srivastava

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Chronic low-grade inflammation has emerged as a key contributor to the cardiovascular complications of diabetes, however, the mechanisms by which diabetes increases inflammation remain poorly understood. Here, we report that exposure to high glucose (HG) stimulates ectodomain shedding of TNF-α from rat aortic smooth muscle cells in culture. Our results show that exposure to HG decreases membrane-associated TNF-α. This decrease in unprocessed TNF-α was prevented by the aldose reductase (AR) inhibitor sorbinil and AR small interference RNA. Treatment with HG, but not equimolar mannitol or 3-O-methyl glucose, resulted in phosphorylation and activation of TNF-α converting enzyme (TACE) (ADAM 17), which were attenuated by sorbinil or AR-specificsmall interference RNA. HG-induced TACE phosphorylation and TNF-α processing were also prevented by TNF-α protease inhibitor-1, an inhibitor of TACE. Inhibition of protein kinase C (PKC)-δ by rottlerin prevented HG-induced TACE activation and the accumulation of unprocessed TNF-α. Treatment with sorbinil decreased elevated levels of circulating TNF-α in streptozotocin-treated diabetic rats. Sorbinil treatment also decreased the expression of TNF-α, matrix metalloproteinase-2, matrix metalIoproteinase-9, and increased tissue inhibitor of metalloproteinase-3 in vascular smooth muscle cells treated with HG and in balloon-injured carotid arteries of diabetic rats. These results indicate that HG-induced TNF-α shedding could be attributed to TACE activation, which is regulated, in part, by PKC-δ and AR. Therefore, inhibition of TACE by TNF-α protease inhibitor-1, or pharmacological inhibition of PKC-δ or AR may represent useful strategies fortreating vascular inflammation associated with diabetes.

Original languageEnglish (US)
Pages (from-to)63-74
Number of pages12
JournalEndocrinology
Volume150
Issue number1
DOIs
StatePublished - Jan 1 2009

ASJC Scopus subject areas

  • Endocrinology

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