The findings that circulating levels of atrial natriuretic peptide (ANP) are elevated in diabetic nephropathy and that the magnitude of the urinary excretion rate of cGMP in response to hypervolemia-induced ANP release is blunted have recently been reported. The purpose of this study was to determine whether these abnormalities are associated with the down-regulation of ANP receptors. Because biologically active (A) ANP receptors in the kidney are inaccessible, we have examined the binding of (125I alpha)ANP to clearance (C) receptors on platelets obtained from patients with diabetic nephropathy. Scatchard analysis revealed a reduction in such binding sites compared with those in healthy controls: 12 +/- 2 versus 19 +/- 2 per platelet, respectively (P less than 0.001). The dissociation constant, Kd, was higher: 66.7 +/- 33.1 versus 38.5 +/- 11 pM, respectively (P less than 0.02). The reduced number of receptors could reflect the down-regulation of ANP C receptors in response to an elevation of plasma levels of ANP, the median value of which was 10.6 versus 7.1 pmol/L in controls (P less than 0.05). Alternatively, the findings could represent a primary adaptation by C receptors to elevate plasma ANP levels and increase the availability of the peptide to biologically active renal receptors. The latter adaptation would serve to mitigate the sodium retention that attends diabetic nephropathy.