Catecholamines block 2-hydroxyestradiol-induced antimitogenesis in mesangial cells

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

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)854-859
Number of pages6
JournalHypertension
Volume39
Issue number4
DOIs
Publication statusPublished - 2002

Keywords

  • Catecholamines
  • Estrogen
  • Glomerulosclerosis
  • Metabolism
  • Renal disease
  • Sympathetic nervous system

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