ROLE FOR LOCAL PROSTAGLANDIN AND THROMBOXANE PRODUCTION IN THE REGULATION OF GLOMERULAR-FILTRATION RATE IN THE RAT WITH STREPTOZOCIN-INDUCED DIABETES

  • 1 June 1989
    • journal article
    • research article
    • Vol. 113  (6) , 674-681
Abstract
We examined the relationship between glomerular filtration rate (GFR), as assessed by inulin clearance, and glomerular prostaglandin and thromboxane production as a function of glycemic control in control rats and rats that had had streptozocin-induced diabetes for 2 months. In severely hyperglycemic (plasmic glucose level 644 .+-. 40 mg/dl) rats with streptozocin-induced diabetes that had not been treated with insulin, GFR was reduced to values below those in control rats by 2 months, whether data were expressed as milliliters per minute or as a function of kidney weight. By contrast, treatment of the diabetic rats with insulin to maintain moderate hyperglycemia (plasma glucose concentration 398 .+-. 40 mg/dl) resulted in a persistent elevation of GFR compared with values in control rats. Basal production of prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1.alpha. (6-keto-PGF1.alpha.), the stable metabolic product of prostaglandin I2 (PGI2), by glomeruli isolated from the moderately hyperglycemic rats was higher than corresponding values of glomeruli from control rats. Differences in PGE2 and 6-keto-PGF1.alpha. production by glomeruli from moderately hyperglycemic and control rats were abolished by addition of arachidonate to the incubation mixture, supporting a role for enhanced availability of arachidonate in the mediation of altered vasodilatory prostaglandin production. By contrast, glomerular production of thromboxane B2 (TXB2), the stable metabolic product of thromboxane A2 (TXA2), was not different in moderately hyperglycemic rats compared with controls. Thus, enhanced production of vasodilatory prostaglandins by glomeruli from moderately hyperglycemic rats was associated with an increase in GFR. Treatment of these rats with aspirin for 2 months significantly reduced GFR and glomerular prostanoid production, thereby implying that enhanced glomerular prostanoid production contributes to the increase in GFR. By contrast, TXB2 production by glomeruli from the severely hyperglycemic rats was higher both basally and in the presence of arachidonate compared with values of either control glomeruli or glomeruli from rats with moderate hyperglycemia. Glomerular PGF2 and 6-keto-PGF1.alpha. production by glomeruli from rats with severe hyperglycemia was not different from control values. Thus, increased glomerular TXB2 production was associated with a decline in GFR at 2 months in severely hyperglycemic rats. Treatment of these rats with either aspirin or with dazoxiben, a selective inhibitor of thromboxane synthesis, increased GFR and inhibited glomerular TXB2 production to values that were not different from those in control rats. The results suggest that both vasodilatory prostaglandins (PGE2 and PGI2) and TXA2 contribute to alterations in GFR that occur in the rat with streptozocin-induced diabetes.