Aldose reductase gene expression and osmotic dysregulation in cultured human retinal pigment epithelial cells

A "compatible osmolyte hypothesis" proposes that intracellular nonionic organic osmolytes such as sorbitol, myo-inositol, taurine, betaine, and glycerophosphorylcholine respond coordinately to changes in external osmolality, thereby maintaining the intracellular ionic milieu. Osmoregulation may be the primary physiological function of aldose reductase, which catalyzes the conversion of glucose to sorbitol. Glucose-induced sorbitol accumulation in isosmotic hyperglycemic states is associated with compensatory depletion of myo-inositol and taurine. Because such depletion may predispose to chronic diabetic complications, the relationship between osmolyte shifts and aldose reductase gene expression was studied in two human retinal pigment epithelial cell lines, one exhibiting osmoregulated and the other high basal aldose reductase gene expression. High basal expression of the aldose reductase gene was associated with rapid sorbitol accumulation and myo-inositol depletion 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 mannitol). Thus the pattern of response of myo-inositol to hyperglycemic and hyperosmotic levels of glucose and mannitol was related to the degree of basal aldose reductase gene expression, which may therefore influence the development of diabetic complications.