Effects of Orotate Administration on the Normal Rat Kidney: Similarity to Changes Observed in Diabetes Mellitus

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Abstract
Glomerular filtration rate, tubular reabsorptive capacity, and renal size are increased early in the course of human insulin-dependent diabetes mellitus. In short-term experimental diabetes in rats, renal weight, total protein, and RNA content are greater than in control rats. These changes are associated with a 12% increase in the cortical uridine 5-triphosphate (UTP)/DNA ratio. We measured the UTP content in the renal cortex of long-term diabetic rats and studied the effects of long-term orotate feeding (0.5%) as a means of UTP pool expansion. Rats with streptozotocin-induced diabetes for six months had a 42% increase in serum creatinine concentration and an 18% increase in width of the glomerular basement membrane (GBM). Renal cortex UTP/DNA/kg was 54% higher than in control rats. Long-term orotate feeding of diabetic rats produced further deterioration of function and increase in basement membrane width. All diabetic animals developed cataracts bilaterally. Chronic orotate feeding in nondiabetic animals produced thickening of the GBM when compared with age-matched controls (2330 ± 24 vs. 2056 ± 16 Å; P < 0.01) that were morphologically undistinguishable from diabetic GBM. UTP/DNA/kg body weight were no different from control values. Chronic orotate feeding for 15 mo was associated with a higher renal cortex glycogen content and an increase in creatinine clearance. No animal in this group had cataracts. Orotate feeding did not change plasma concentrations of glucose or insulin and was associated with increased glucagon concentrations in both diabetic and nondiabetic rats. We postulate that the renal changes induced by orotate, which resemble those of diabetes, are mediated through alterations in pyrimidine metabolism.