Estradiol and Its Metabolites Differentially Induce NO Synthesis by Human Glomerular Endothelial Cells and Inhibit Glomerular Mesangial Cell Growth
Reduced NO synthesis by glomerular endothelial cells (GECs) and increased proliferation of glomerular mesangial cells (GMCs) is associated with glomerular remodeling process leading to glomerosclerosis. Moreover, estradiol (E) slows the progression of renal disease. Because E induces NO synthesis and E metabolites are as potent as E in inhibiting growth of vascular smooth muscle cells, which are phenotypically similar to GMCs, we investigated whether E and its major endogenous metabolites (2-hydroxyestradiol[2OHE] and 2-methoxyestradiol [2MeOE])inhibit growth of GMCs and induce basal NO synthesis by GECs. E and its metabolites (1nM-10μM)inhibited serum (2.5%)-induced DNA synthesis, cell number and collagen synthesis in human GMCs concentration-dependently,and with the order of potency being 2MeOE > 2OHE > E. ICI182780, an estrogen receptor antagonist (100μM) blocked the growth inhibitory effects of E, but not 2OHE and 2MeOE. Treatment with E, but not 2OHE and 2MeOE, induced NO synthesis (P<.05; assayed by the formation of 3H-L-citrulline from 3H-L-arginine) in human GECs, and these effects were blocked by ICI182780 and L-NMA (NO synthesis inhibitor).In conclusion, E may protect glomerosclerosis by inducing NO synthesis via an estrogen receptor-dependent mechanism and via conversion to 2OHE and 2MeOE, which inhibit GMC proliferation independently of the estrogen receptor.