Functional implications of decreased renal cortical atrial natriuretic peptide binding in experimental diabetes

Abstract

Glomerular hyperfiltration in streptozotocin-induced diabetes mellitus in rats may be mediated by atrial natriuretic peptide (ANP). We wanted to evaluate plasma levels of ANP and plasma volume in relation to renal ANP receptor density and affinity in rats 6 weeks after induction of diabetes. Plasma levels of immunoreactive ANP were significantly higher in hyperglycemic diabetic (75.2 ± 8.3 pg/ml) than in control animals (34.7 ± 8.1 pg/ml; p < 0.01). Administration of insulin to keep diabetic rats normoglycemic normalized plasma levels of immunoreactive ANP (30.5 ± 5.2 pg/ml). In contrast, plasma volume did not show significant differences among the groups (hyperglycemic diabetes, 46.6 ± 3.8; normoglycemic diabetes, 42.4 ± 3.2; controls, 43.2 ± 2.0 ml/kg body wt). No correlation was found between plasma levels of immunoreactive ANP and plasma volume. By autoradiography a significant reduction in the number of renal cortical ANP receptors was observed in hyperglycemic diabetic rats as compared with controls. At variance, ANP receptor affinity did not change either in the cortex or in the medulla in hyperglycemic diabetics in comparison with control animals. The pathophysiological implication of cortical ANP receptor down-regulation was underscored by the blunted response of glomerular filtration rate to ANP infusion in diabetic animals as compared with controls. These results indicate that in hyperglycemic diabetic rats: 1) the plasma volume is numerically higher without reaching a statistically significant value and does not correlate with the elevated plasma levels of ANP; 2) the marked rise in plasma concentration of ANP is associated with a significant reduction in the density of ANP binding sites in the renal cortex, without measurable changes in medullary receptors; and 3) the blunted glomerular hemodynamic response to ANP infusion underscores the importance of down-regulation of cortical ANP receptors in modulating the sustained hyperfiltration of early diabetes.