TY - JOUR
T1 - Catecholamines block 2-hydroxyestradiol-induced antimitogenesis in mesangial cells
AU - Zacharia, Lefteris C.
AU - Jackson, Edwin K.
AU - Gillespie, Delbert G.
AU - Dubey, Raghvendra K.
PY - 2002
Y1 - 2002
N2 - 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 Vmax of 12.03±0.32 pmol/106 cells/min and an apparent Km of 0.23±0.04 μmol/L. Norepinephrine (10 μmol/L) and epinephrine (10 μmol/L) significantly inhibited methylation of 0.25 μmol/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 μmol/L norepinephrine, the inhibitory effect of 0.1 μmol/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.
AB - 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 Vmax of 12.03±0.32 pmol/106 cells/min and an apparent Km of 0.23±0.04 μmol/L. Norepinephrine (10 μmol/L) and epinephrine (10 μmol/L) significantly inhibited methylation of 0.25 μmol/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 μmol/L norepinephrine, the inhibitory effect of 0.1 μmol/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.
KW - Catecholamines
KW - Estrogen
KW - Glomerulosclerosis
KW - Metabolism
KW - Renal disease
KW - Sympathetic nervous system
UR - http://www.scopus.com/inward/record.url?scp=0036241168&partnerID=8YFLogxK
U2 - 10.1161/01.HYP.0000014502.44988.39
DO - 10.1161/01.HYP.0000014502.44988.39
M3 - Article
C2 - 11967239
AN - SCOPUS:0036241168
SN - 0194-911X
VL - 39
SP - 854
EP - 859
JO - Hypertension
JF - Hypertension
IS - 4
ER -