We observed a general trend toward downregulation of
ALDH and
AKR gene expression in the retina during diabetes. These findings are consistent with the proposal that, in addition to increased oxidative stress and lipoxidation, the impairment of lipid aldehyde defense mechanisms also may contribute to the accumulation of toxic aldehydes and ALEs in the diabetic retina. These results are similar to those reported previously in the heart, where downregulation of certain ALDH enzymes has been implicated in the accumulation of lipid aldehydes and the development of cardiomyopathy during experimental diabetes.
57 Loss of ALDH activity also has been suggested to have a role in the diabetes-induced accumulation of lipid aldehydes in the liver,
58 although whether this occurs through a reduction in the expression of these enzymes or results from their direct inhibition by the diabetic milieu remains to be determined. In contrast to the retina, diabetes triggered upregulation of many of the ALDH and AKR enzymes examined in the lens and cornea. It is unclear why diabetes exerts opposing actions on
ALDH and
AKR gene expression in different tissues of the eye. Previous studies have shown that a number of the
ALDH and
AKR genes are downstream targets of the transcription factor, Nrf2,
59 which regulates the constitutive and inducible transcription of a wide range of antioxidant defense genes.
60 During diabetes, however, Nrf2 activity has been reported to be repressed in the retina and the lens,
61,62 and, therefore, differential activation of this pathway in these tissues is unlikely to explain the differences in
ALDH and
AKR gene expression observed in the present study. Other studies have suggested that certain lipid aldehyde detoxifying
ALDH and
AKR genes may be regulated at the transcriptional level by the transcription factors, AP-1,
63 NFY,
64 NFAT-5,
65 and hStaf/ZNF143,
66 and posttranscriptionally by miR-28.
67 Clearly, it will be of interest in the future to examine whether variable activation/inhibition of these pathways underlies the heterogeneous effects of diabetes on
ALDH and
AKR gene expression in the retina when compared to the lens and cornea.