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(Hypertension. 2002;39:854.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Catecholamines Block 2-Hydroxyestradiol-Induced Antimitogenesis in Mesangial Cells

Lefteris C. Zacharia; Edwin K. Jackson; Delbert G. Gillespie; Raghvendra K. Dubey

From the Center for Clinical Pharmacology, Departments of Medicine (E.K.J., D.G.G., R.K.D.) and Pharmacology (L.C.Z., E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, Pa; and the Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich (R.K,D.), Switzerland.

Correspondence to Dr Raghvendra K. Dubey, Department of Obstetrics and Gynecology, Clinic for Endocrinology, D217 NORD-1, Frauenheilkunde, University Hospital Zurich, Zurich, 8091 - CH, Switzerland. E-mail rag{at}fhk.usz.ch

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/10⁶ cells/min and an apparent K_m 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.

Key Words: estrogen • catecholamines • metabolism • sympathetic nervous system • renal disease • glomerulosclerosis