Effects of estradiol and its metabolites on glomerular endothelial nitric oxide synthesis and mesangial cell growth

Reduced nitric oxide synthesis by glomerular endothelial cells and increase d 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 3-methoxyestradiol are mo re potent than estradiol in inhibiting growth of vascular smooth muscle cel ls, which are phenotypically similar to mesangial cells, we compared the ef fects of estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol on growth of glomerular mesangial cells and on basal nitric oxide synthesis by glomerul ar endothelial cells. In human glomerular mesangial cells, estradiol and it s metabolites concentration-dependently (1 nmol/L to 10 mu mol/L) inhibited serum (2.5%)-induced DNA synthesis, cell proliferation, and collagen synth esis with the order of potency being 2-methoxyestradiol > 2-hydroxyestradio l > estradiol. ICI182780 (100 mu mol/L, an estrogen receptor antagonist) bl ocked the growth inhibitory effects of estradiol but not 2-hydroxyestradiol or 2-methoxyestradiol. Treatment with estradiol. but not 2-hydroxpestradio l and 2-methoxyestradiol, induced nitric oxide synthesis (P<0.05, assayed b y the formation of H-3-L-citrulline from H-3-L-arginine) in human glomerula r 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 rece ptor-dependent mechanism and by conversion to 2-hydroxyestradiol and 2-meth oxyestradiol, which inhibit glomerular mesangial cell proliferation indepen dent of estrogen receptors.