Apparent B-type natriuretic peptide selectivity in the kidney due to differential processing

Two natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natri uretic peptide (BNP), are found principally in the heart. In preliminary ex periments with mouse kidney cells or slices, we found mouse BNP1-45 much mo re potent than ANP1-28 in causing elevations of cGMP (> 50-fold). The guany lyl cyclase-A (GC-A) receptor has been suggested to represent the primary m eans by which both peptides signal. In cultured cells overexpressing GC-A, BNP and ANP were almost equivalent in potency, suggesting that a receptor u nique for BNP exists in the kidney. However, in mice lacking the GC-A gene, neither BNP nor ANP significantly elevated cGMP in kidney slices. Phosphor amidon, a neutral endopeptidase inhibitor, shifted the apparent potency of ANP to values equivalent to that of BNP, suggesting these kidney cell/slice s rapidly degrade ANP but not BNP. Mass spectroscopic analysis confirmed th at ANP is rapidly cleaved at the first cysteine of the disulfide ring, wher eas BNP is particularly stable to such cleavage. Other tissues (heart, aort a) failed to significantly degrade ANP or BNP, and therefore the kidney-spe cific degradation of ANP provides a mechanism for preferential regulation o f kidney function by BNP independent of peripheral ANP concentration.