DOWN-REGULATION OF ATRIAL-NATRIURETIC-FACTOR CLEARANCE RECEPTORS IN EXPERIMENTAL CHRONIC-RENAL-FAILURE RATS

Studies were performed to examine the changes of renal ANF second messenger guanosine 3',5'-cyclic monophosphate (cGMP) responses and receptor properties in chronic renal failure (CRF). Five-sixths-nephrectomized and sham-operated Wistar rats were used. The glomerular filtration rate was decreased in the five-sixths-nephrectomized rats, which also had significantly higher plasma blood urea nitrogen and plasma atrial natriuretic factor (ANF) levels (148.5 +/- 10.2 vs. 115.7 +/- 7.3 pg/ml, P = 0.01) than the sham rats. In vitro ANF-stimulated cGMP accumulations in glomeruli of five-sixths-nephrectomized rats were higher than controls. Radioligand-binding experiments showed downregulation of the total ANF receptor in both acid and nonacid wash CRF glomeruli (nonacid wash: 189 +/- 25 vs. 362.8 +/- 52.8 fmol/mg protein, P < 0.05; acid wash: 449.8 +/- 67 vs. 652.7 +/- 52.5 fmol/mg protein, P < 0.05). No change in receptor densities was observed in the des(Gln(18),Ser(19),Gly(20),Leu(21))atrial natriuretic peptide-(4-23)-NH2-resistant receptors between sham and CRF rat glomeruli. Therefore, downregulation of ANF clearance receptors exists in CRF rat glomeruli, and this is associated with the exaggerated ANF-stimulated cGMP response in these CRF glomeruli. Hypersensitivity of CRF rat to ANF, together with high plasma ANF levels and downregulation of clearance receptor, may contribute to increased sodium excretion in CRF.