ALDOSE REDUCTASE GENE-EXPRESSION AND OSMOTIC DYSREGULATION IN CULTURED HUMAN RETINAL-PIGMENT EPITHELIAL-CELLS

A ''compatible osmolyte hypothesis' proposes that intracellular nonion ic organic osmolytes such as sorbitol, myo-inositol, taurine, betaine, and glycerophosphorylcholine respond coordinately to changes in exter nal osmolality, thereby maintaining the intracellular ionic milieu. Os moregulation may be the primary physiological function of aldose reduc tase, which catalyzes the conversion of glucose to sorbitol. Glucose-i nduced sorbitol accumulation in isosmotic hyperglycemic states is asso ciated with compensatory depletion of myo-inositol and taurine. Becaus e such depletion may predispose to chronic diabetic complications, the relationship between osmolyte shifts and aldose reductase gene expres sion was studied in two human retinal pigment epithelial cell lines, o ne exhibiting osmoregulated and the other high basal aldose reductase gene expression. High basal expression of the aldose reductase gene wa s associated with rapid sorbitol accumulation and myo-inositol depleti on in response to hyperglycemic (20 mM) concentrations of glucose. Myo -inositol and sorbitol behaved as compensating intracellular osmolytes by accumulating markedly in response to hyperosmolality (300 mM manni tol). Thus the pattern of response of myo-inositol to hyperglycemic an d hyperosmotic levels of glucose and mannitol was related to the degre e of basal aldose reductase gene expression, which may therefore influ ence the development of diabetic complications.