Evolutionarily, adaptation to hyperosmotic stress through accumulation of osmotically active organic solutes (organic osmolytes) is a highly conserved mechanism. Hyperosmotic accumulation of organic osmolytes is transcriptionally regulated: e.g., betaine in bacteria (e.g., Escherichia coli), glycerol in yeast (e.g., Saccharomyces cerevisiae), betaine in plants (e.g., Spinacea oleracea L.) and sorbitol, betaine, and inositol in cells of the mammalian renal medulla. Renal medullary cells, among mammalian cells, are uniquely exposed to hyperosmotic stress; in these cells, hyperosmotic stress results in accumulation of sorbitol as one of the predominant osmolytes. Sorbitol accumulates due to a rise in the synthesis rate of aldose reductase (AR), which catalyzes the conversion of glucose to sorbitol. Hyperosmotic stress increases transcription of the AR gene which leads to a rise in AR mRNA levels. In cloning and characterizing the rabbit AR gene, the first evidence of a eukaryotic osmotic response element (ORE) was found. Since then, several mammalian OREs (also called TonE) have been discovered. Sequence containing an ORE was identified for the canine Na - and Cl⁻-coupled betaine transporter gene as well as the Na /myo-inositol cotransporter gene. Because it is possible to find homology between the OREs of the AR genes and those of the betaine and inositol genes, a consensus for the mammalian ORE was derived by functional assessment. Most recent studies have resulted in the discovery of other cis-elements that potentiate the ORE response and a trans-activating factor that binds to the ORE.