Catecholamines block 2-hydroxyestradiol-induced antimitogenesis in mesangial cells.
Methylation of 2-hydroxyestradiol to 2-methoxyestradiol by catechol-O-methyl transferase (COMT) mediates the antimitogenic effects of 2-hydroxyestradiol on vascular smooth muscle cells. Moreover, 2-hydroxyestradiol inhibits growth of glomerular mesangial cells (GMCs). Because catecholamines are substrates for COMT, which is expressed in GMCs, we hypothesize that catecholamines may abrogate the antimitogenic effects of 2-hydroxyestradiol on GMCs by competing for COMT and inhibiting 2-methoxyestradiol formation. To test this hypothesis, we investigated the antimitogenic effects of 2-hydroxyestradiol on rat GMCs in the presence and absence of catecholamines. The capability of GMCs to methylate 2-hydroxyestradiol in the presence and absence of catecholamines was also evaluated. GMCs metabolized 2-hydoxyestradiol in a concentration-dependent manner with a V(max) of 12.03+/-0.32 pmol/10(6) cells/min and an apparent K(m) of 0.23+/-0.04 micromol/L. Norepinephrine (10 micromol/L) and epinephrine (10 micromol/L) significantly inhibited methylation of 0.25 micromol/L 2-hydroxyestradiol. Norepinephrine concentration-dependently abrogated the ability of 2-hydroxyestradiol to inhibit 3H-thymidine incorporation (index of DNA synthesis). In the presence of 5, 10, and 40 micromol/L norepinephrine, the inhibitory effect of 0.1 micromol/L 2-hydroxyestradiol on 3H-thymidine incorporation was reduced from 51+/-0.7% to 46+/-0.4%, 39+/-0.3%, and 25+/-0.7%, respectively. Similar to DNA synthesis, the inhibitory effects of 2-hydroxyestradiol on cell number and 3H-proline incorporation (index of collagen synthesis) on GMCs were abrogated by catecholamines. Our findings provide evidence that methylation of 2-hydroxyestradiol inhibits GMC proliferation and extracellular matrix synthesis and may in part protect against renal proliferative diseases. Moreover, catecholamines may abrogate the renoprotective effects of 2-hydroxyestradiol in the glomeruli by inhibiting COMT and 2-methoxyestradiol formation.
Zacharia
Lefteris C
LC
Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa, USA.
Jackson
Edwin K
EK
Gillespie
Delbert G
DG
Dubey
Raghvendra K
RK
D000077584:2-Methoxyestradiol; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D011392:Proline / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013936:Thymidine / Q000378:metabolism
D002395:Catecholamines; D004965:Estrogen Antagonists; D006131:Growth Inhibitors; D004958:Estradiol; D000077584:2-Methoxyestradiol; D011392:Proline; C001390:2-hydroxyestradiol; D013936:Thymidine