(Hypertension. 2001;37:645.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Effects of Estradiol and Its Metabolites on Glomerular Endothelial Nitric Oxide Synthesis and Mesangial Cell Growth
From the Center for Clinical Pharmacology, Departments of Medicine (D.G.G., E.K.J., R.K.D.) and Pharmacology (E.K.J.), University of Pittsburgh, Penn; Department of Physiology (S.X., C.B.), West Virginia University, Morgantown; and Clinic for Endocrinology, Department of Obstetrics and Gynecology (R.K.D.), University Hospital Zurich, Switzerland.
Correspondence to Dr Raghvendra K. Dubey, D217, NORD-1, Clinic for Endocrinology, Department of Obstetrics and Gynecology, Frauenklinik, Zurich 8091, Switzerland. E-mail rag{at}fhk.usz.ch
Reduced nitric oxide synthesis by glomerular endothelial cells and increased proliferation of glomerular mesangial cells is associated with glomerular remodeling that leads to accelerated glomerulosclerosis. Estradiol induces nitric oxide synthesis and slows the progression of renal disease. Because the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol are more potent than estradiol in inhibiting growth of vascular smooth muscle cells, which are phenotypically similar to mesangial cells, we compared the effects of estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol on growth of glomerular mesangial cells and on basal nitric oxide synthesis by glomerular endothelial cells. In human glomerular mesangial cells, estradiol and its metabolites concentration-dependently (1 nmol/L to 10 µmol/L) inhibited serum (2.5%)-induced DNA synthesis, cell proliferation, and collagen synthesis with the order of potency being 2-methoxyestradiol > 2-hydroxyestradiol > estradiol. ICI182780 (100 µmol/L, an estrogen receptor antagonist) blocked the growth inhibitory effects of estradiol but not 2-hydroxyestradiol or 2-methoxyestradiol. Treatment with estradiol, but not 2-hydroxyestradiol and 2-methoxyestradiol, induced nitric oxide synthesis (P<0.05, assayed by the formation of 3H-L-citrulline from 3H-L-arginine) in human glomerular endothelial cells, and these effects were blocked by ICI182780 and L-NMA (a nitric oxide synthesis inhibitor). In conclusion, estradiol may attenuate glomerulosclerosis by inducing nitric oxide synthesis via an estrogen receptor–dependent mechanism and by conversion to 2-hydroxyestradiol and 2-methoxyestradiol, which inhibit glomerular mesangial cell proliferation independent of estrogen receptors.
Key Words: 2-hydroxyestradiol • nitric oxide • 2-methoxyestradiol • glomerulosclerosis • renal disease, end-stage • postmenopause
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