TY - JOUR
T1 - Catecholamines block the antimitogenic effect of estradiol on human glomerular mesangial cells
AU - Dubey, Raghvendra K.
AU - Zacharia, Lefteris C.
AU - Gillespie, Delbert G.
AU - Imthurn, Bruno
AU - Jackson, Edwin K.
PY - 2003/9/1
Y1 - 2003/9/1
N2 - Local sequential conversion of estradiol to hydroxyestradiols and methoxyestradiols by CYP450 and catechol-O-methyltransferase, respectively, contributes to the antimitogenic effects of estradiol on glomerular mesangial cell growth via estrogen receptor-independent mechanisms. Catecholamines are also substrates for catechol-O-methyltransferase and therefore, might abrogate the renoprotective effects of estradiol by inhibiting formation of methoxyestradiols. To test this hypothesis, we investigated the antimitogenic effects of estradiol on human glomerular mesangial cell proliferation and collagen synthesis in the presence and absence of catecholamines. Norepinephrine, epinephrine, and isoproterenol abrogated the inhibitory effects of estradiol on cell number, DNA synthesis, and collagen synthesis. For example, serum-induced DNA synthesis was inhibited from 100% to 62±1.9% by 0.1 μmol/L estradiol, and these inhibitory effects were reversed to 91±1.9% by 1 μmol/L epinephrine, 90.7±3.3% by 1 μmol/L isoproterenol, 87.5±2.8% by 10 μmol/L norepinephrine, and 92±1% by 10 μmol/L OR486 (catechol-O-methyltransferase inhibitor). The interaction of catecholamines with estradiol was not affected by phentolamine or propanolol, α- and β-adrenoceptor antagonists, respectively. Similar to estradiol, the antimitogenic effects of 2-hydroxyestradiol were abrogated by epinephrine, isoproterenol, and OR486. In contrast to estradiol and 2-hydroxyestradiol, the antimitogenic effects of 2-methoxyestradiol were not attenuated by epinephrine, isoproterenol, or OR486. Norepinephrine, epinephrine, and isoproterenol inhibited the conversion of both estradiol and 2-hydroxyestradiol to 2-methoxyestradiol. Our findings suggest that catecholamines within the glomeruli might abrogate the antimitogenic effects of estradiol by blocking the conversion of 2-hydroxyestradiol to 2-methoxyestradiol.
AB - Local sequential conversion of estradiol to hydroxyestradiols and methoxyestradiols by CYP450 and catechol-O-methyltransferase, respectively, contributes to the antimitogenic effects of estradiol on glomerular mesangial cell growth via estrogen receptor-independent mechanisms. Catecholamines are also substrates for catechol-O-methyltransferase and therefore, might abrogate the renoprotective effects of estradiol by inhibiting formation of methoxyestradiols. To test this hypothesis, we investigated the antimitogenic effects of estradiol on human glomerular mesangial cell proliferation and collagen synthesis in the presence and absence of catecholamines. Norepinephrine, epinephrine, and isoproterenol abrogated the inhibitory effects of estradiol on cell number, DNA synthesis, and collagen synthesis. For example, serum-induced DNA synthesis was inhibited from 100% to 62±1.9% by 0.1 μmol/L estradiol, and these inhibitory effects were reversed to 91±1.9% by 1 μmol/L epinephrine, 90.7±3.3% by 1 μmol/L isoproterenol, 87.5±2.8% by 10 μmol/L norepinephrine, and 92±1% by 10 μmol/L OR486 (catechol-O-methyltransferase inhibitor). The interaction of catecholamines with estradiol was not affected by phentolamine or propanolol, α- and β-adrenoceptor antagonists, respectively. Similar to estradiol, the antimitogenic effects of 2-hydroxyestradiol were abrogated by epinephrine, isoproterenol, and OR486. In contrast to estradiol and 2-hydroxyestradiol, the antimitogenic effects of 2-methoxyestradiol were not attenuated by epinephrine, isoproterenol, or OR486. Norepinephrine, epinephrine, and isoproterenol inhibited the conversion of both estradiol and 2-hydroxyestradiol to 2-methoxyestradiol. Our findings suggest that catecholamines within the glomeruli might abrogate the antimitogenic effects of estradiol by blocking the conversion of 2-hydroxyestradiol to 2-methoxyestradiol.
KW - Catecholamines
KW - Estrogen
KW - Glomerulosclerosis
KW - Metabolism
KW - Peptides
KW - Renal disease
UR - http://www.scopus.com/inward/record.url?scp=0041331771&partnerID=8YFLogxK
U2 - 10.1161/01.HYP.0000088320.81260.26
DO - 10.1161/01.HYP.0000088320.81260.26
M3 - Article
C2 - 12913061
AN - SCOPUS:0041331771
SN - 0194-911X
VL - 42
SP - 349
EP - 355
JO - Hypertension
JF - Hypertension
IS - 3
ER -