IDENTIFICATION AND CHARACTERIZATION OF MULTIPLE OSMOTIC RESPONSE SEQUENCES IN THE HUMAN ALDOSE REDUCTASE GENE

Aldose reductase (AR) has been implicated in osmoregulation in the kid ney because it reduces glucose to sorbitol, which can serve as an osmo lite. Under hyperosmotic stress, transcription of this gene is induced to increase the enzyme level. This mode of osmotic regulation of AR, gene expression has been observed in a number of nonrenal cells as wel l, suggesting that this is a common response to hyperosmotic stress. W e have identified a 132-base pair sequence similar to 1 kilobase pairs upstream of the transcription start site of the AR gene that enhances the transcription activity of the AR promoter as well as that of the SV40 promoter when the cells are under hyperosmotic stress. Within thi s 132-base pair sequence, there are three sequences that resemble TonE , the tonicity response element of the canine betaine transporter gene , and the osmotic response element of the rabbit AR gene, suggesting t hat the mechanism of osmotic regulation of gene expression in these an imals is similar. However, our data indicate that cooperative interact ion among the three TonE-like sequence's in the human AR may be necess ary for their enhancer function.