A Role of Gene Expression of Aldose Reductase in the Development of Diabetic Complications

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The accumulation of sorbitol in various tissues has been speculated to play an important role in the development of diabetic complications such as neuropathy, retinopathy, and nephropathy. At the moment, the rate of sorbitol production is understood to be modulated mainly by the amount of glucose, the substrate of aldose reductase, an enzyme to convert glucose to sorbitol. However, the role of aldose reductase itself in the rate of sorbitol production has not been well defined. In this research the gene expression of aldose reductase in rat glomerular mesangial cells was investigated in an attempt to clarify the role of aldose reductase in the regulation of the rate of sorbitol production. Using cDNA (10Q) for rat lens aldose reductase the presence of aldose reductase mRNA was confirmed in these cells. The activity of aldose reductase was markedly increased when mesangial cells were incubated in the medium containing large amount of osmolytes ( plus 300 mOsmoles of NaCL ), indicating that the osmolarity may be the factor to modulate the gene expression of aldose reductase as prevously reported in renal medullary cells. However, neither glucose in high concentration or IGF-I, both increased in diabetes mellitus, was able to alter the activity of aldose reductase. Furthermore, the amount of mRNA for aldose reductase in renal glomeruli was not increased in diabetic rats compared to that of control rats.In summary, the gene expression of aldose reductase is unlikely to modulate the rate of sorbitol production in diabetic state, although some abnormalities in aldose reductaseー or its related gene may exist and cause the different severity of diabetic complications between patient to patient