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S.K. Srivastava, A. Pladzyk, K.V. Ramana; Aldose Reductase Prevents Lipid Aldehyde Toxicity in Cultured Human Lens Epithelial Cells . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3860.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We have shown that aldose reductase (AR) besides reducing glucose to sorbitol, efficiently reduces various toxic lipid derived aldehydes (LDAs), generated under oxidative stress, with Km in the physiological range. The purpose of this investigation was to identify the role of AR in the prevention of various LDAs –induced cytotoxic signals leading to apoptosis in human lens epithelial cells (HLEC). Methods: Growth– arrested HLEC were cultured without or with AR inhibitors or transfected with an AR over–expressing vector. Subsequently, the cells were stimulated with various saturated and unsaturated lipid aldehydes with a carbon chain length varying from C3 to C10 (0–10 µM). The cell viability was assessed by cell counts and MTT assay and the apoptosis was measured by nucleosomal degradation and DNA laddering. Caspase–3 activation was measured by using a specific ELISA kit. Western blot analysis was performed to measure the activation of MAPK, JNK and Bcl–2 family of proteins using respective antibodies. Results: Various LDAs caused apoptosis of HLEC. However, no significant difference was observed in the apoptosis caused by short chain and long chain saturated or unsaturated aldehydes. The unsaturated aldehydes were more toxic than saturated aldehydes. Inhibition of AR by two structurally unrelated inhibitors – sorbinil and tolrestat, potentiated while the over–expression of AR prevented the apoptosis induced by various LDAs. AR over–expression also prevented the LDA–induced activation of caspase–3, MAPK, JNK and the expression of Bcl–2 family of proteins in HLEC. Conclusions: The results indicate that the LDAs generated under oxidative stress are cytotoxic to HLEC as determined by increased apoptosis and that the reduction of LDAs by AR prevents it.
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