Polyhydric alcohols, or polyols, are osmotically active organic molecules whose physiologic and pathophysiologic significance has only very recently come under investigation. These molecules are produced by the reduction of common sugars via the catalytic action of aldose reductase. It appears that the overproduction and accumulation of polyols such as sorbitol, the product of glucose reduction, in certain tissues, may be responsible for some of the dire consequences of chronic hyperglycemia, as in diabetes mellitus. Polyol accumulation in lens, retina and nerve cells has been associated with osmotic injury and development of cataracts, retinopathy and neuropathy. We have described the cellular localization of aldose reductase mRNA in the rat lens epithelium, retinal Meuller cells, peripheral Schwann cells, ovarian granulosa cells and renal inner medullary epithelium. We have shown that aldose reductase gene expression is regulated by local osmotic pressure, and by end-product accumulation in cells of the renal medulla. We have proposed that the function of aldose reductase catalyzed sorbitol production in the renal medulla is to provide an osmotic buffering system for the protection of medullary epithelial cells against the extremely high and varying ambient osmotic stresses of the renal medulla. We have also hypothesized, as a result of finding extremely high levels of aldose reductase mRNA in developing lens epithelial cells, that aldose reductase catalyzed sorbitol production may drive the huge volume expansion which is the key feature of lens cell differentiation. Future studies will include investigation of the role of aldose and its sister enzyme, aldehyde reductase in normal physiology and in the pathophysiology of diabetes and hereditary galactosemia, focusing on tissues such as kidney, peripheral nerve and ovary, which are primary targets of injury in these diseases. We also will pursue the more basic issue of the phenomenon of osmoregulation of gene expression, using aldose reductase as a model system.
