Novel natriuretic peptide receptor/guanylyl cyclase A-selective agonist inhibits angiotensin II- and forskolin-evoked aldosterone synthesis in a human zona glomerulosa cell line.
We report the production of a novel human natriuretic peptide receptor/guanylyl cyclase A (hNPR-A)-selective agonist ANP [G9T, R11S, G16R] (sANP). This agonist has similar affinity to ANP for hNPR-A and 1,000-10,000-fold reduced affinity for the human natriuretic peptide clearance receptor (hNPR-C). sANP was used to directly test the hypothesis that hNPR-A mediates the inhibitory effect of natriuretic peptides on aldosterone generation in a human zona glomerulosa cell line, H295R. Human type A natriuretic peptide and sANP (10(-11) to 10(-6) M) resulted in concentration-dependent increases in cGMP levels and decreases in forskolin (100 nM)- and angiotensin II (5 nM)-induced aldosterone and pregnenolone production. These results revealed an inhibitory effect of both peptides on the agonist-stimulated conversion of cholesterol to pregnenolone (i.e., cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme, EC 1.14.15.6). H295R cells also exhibited angiotensin II- and forskolin-evoked conversion of [3H]cortico-sterone to [3H]aldosterone (i.e., cytochrome P-450 steroid 11 beta-monooxygenase/aldosterone synthase, EC 1.14.15.4). Human type A natriuretic peptide and sANP (10(-7) M) inhibited the angiotensin II-stimulated late pathway but did not affect forskolin-facilitated conversion of corticosterone to aldosterone. Our results directly demonstrate inhibitory effects of hNPR-A-mediated signal transduction on cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme and steroid 11 beta-monooxygenase/aldosterone synthase complex depending on the steroidogenic agonist used.
Olson
L J
LJ
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Lowe
D G
DG
Drewett
J G
JG
D000450:Aldosterone / Q000096:biosynthesis*; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology*; D003345:Corticosterone / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D017461:Receptors, Atrial Natriuretic Factor / Q000819:agonists*; D015384:Zona Glomerulosa / Q000378:metabolism*
D000804:Angiotensin II; D005576:Colforsin; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D003345:Corticosterone