Apparent B-type natriuretic peptide selectivity in the kidney due to differential processing.
Two natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), are found principally in the heart. In preliminary experiments with mouse kidney cells or slices, we found mouse BNP1-45 much more potent than ANP1-28 in causing elevations of cGMP (>50-fold). The guanylyl cyclase-A (GC-A) receptor has been suggested to represent the primary means by which both peptides signal. In cultured cells overexpressing GC-A, BNP and ANP were almost equivalent in potency, suggesting that a receptor unique for BNP exists in the kidney. However, in mice lacking the GC-A gene, neither BNP nor ANP significantly elevated cGMP in kidney slices. Phosphoramidon, a neutral endopeptidase inhibitor, shifted the apparent potency of ANP to values equivalent to that of BNP, suggesting these kidney cell/slices rapidly degrade ANP but not BNP. Mass spectroscopic analysis confirmed that ANP is rapidly cleaved at the first cysteine of the disulfide ring, whereas BNP is particularly stable to such cleavage. Other tissues (heart, aorta) failed to significantly degrade ANP or BNP, and therefore the kidney-specific degradation of ANP provides a mechanism for preferential regulation of kidney function by BNP independent of peripheral ANP concentration.
Kishimoto
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Howard Hughes Medical Institute, and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75390-9051, USA. ich@kuhp.kyoto-u.ac.jp
Hamra
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Garbers
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D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D019556:COS Cells; D006152:Cyclic GMP / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006868:Hydrolysis; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D009928:Organ Specificity; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000378:metabolism
D011956:Receptors, Cell Surface; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D010450:Endopeptidases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP