Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF-alpha in human lens epithelial cells.

Kota Ramana, Brian Friedrich, Aruni Bhatnagar, Satish Srivastava

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Chronic hyperglycemia and cytokines such as tumor necrosis factor alpha (TNF-alpha) cause oxidative stress leading to dysregulated cell growth or apoptosis that contributes to the development of inflammation and secondary complications of diabetes. However, the mechanisms regulating hyperglycemic or cytokine injury are not well understood. Herein we report that inhibition of the polyol pathway enzyme aldose reductase (AR) by two structurally unrelated inhibitors--sorbinil and tolrestat--prevents, in the human lens epithelial cell line B-3, the apoptosis and activation of caspase-3 caused by exposure to high glucose levels or TNF-alpha. Inhibition of AR attenuated TNF-alpha and hyperglycemia-induced activation of protein kinase C (PKC), phosphorylation of the inhibitory subunit of nuclear factor-kappaB (NF-kappaB), and stimulation of NF-kappaB, but it did not prevent the activation of NF-kappaB and PKC by phorbol ester. Inhibition of AR also attenuated the increase in p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation. These signaling pathways were also inhibited in cells in which the expression of AR was reduced by antisense ablation. Collectively, these results identify a new participant in apoptotic signaling and suggest that AR is an obligatory mediator of the apoptotic events upstream of PKC. These observations could provide new insights into the pathophysiology of diabetes and the role of aberrant glucose metabolism in apoptotic cell death.

Original languageEnglish (US)
Pages (from-to)315-317
Number of pages3
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume17
Issue number2
StatePublished - 2003

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Aldehyde Reductase
Hyperglycemia
Lenses
Tumor Necrosis Factor-alpha
Epithelial Cells
Protein Kinase C
Phosphorylation
Chemical activation
Medical problems
Apoptosis
Cytokines
Glucose
Oxidative stress
JNK Mitogen-Activated Protein Kinases
Cell growth
Phorbol Esters
p38 Mitogen-Activated Protein Kinases
Cell death
Diabetes Complications
Ablation

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Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF-alpha in human lens epithelial cells. / Ramana, Kota; Friedrich, Brian; Bhatnagar, Aruni; Srivastava, Satish.

In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 17, No. 2, 2003, p. 315-317.

Research output: Contribution to journalArticle

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