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Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF‐α in human lens epithelial cells
Author(s) -
Ramana Kota V.,
Friedrich Brian,
Bhatnagar Aruni,
Srivastava Satish K.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0568fje
Subject(s) - sorbinil , aldose reductase , protein kinase c , microbiology and biotechnology , kinase , signal transduction , tumor necrosis factor alpha , biology , apoptosis , endocrinology , programmed cell death , polyol pathway , medicine , cancer research , aldose reductase inhibitor , biochemistry , diabetes mellitus
Chronic hyperglycemia and cytokines such as tumor necrosis factor α (TNF‐α) 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‐α. Inhibition of AR attenuated TNF‐α and hyperglycemia‐induced activation of protein kinase C (PKC), phosphorylation of the inhibitory subunit of nuclear factor‐κB (NF‐κB), and stimulation of NF‐κB, but it did not prevent the activation of NF‐κB 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.