Role of Methoxyestradiols in the Growth Inhibitory Effects of Estradiol on Human Glomerular Mesangial Cells

Metabolism of locally applied 17&bgr;-estradiol (estradiol) to methoxyestradiols contributes to the growth inhibiting effects of estradiol on vascular smooth muscle cells via an estrogen receptor (ER)-independent mechanism. Because vascular smooth muscle cells are phenotypically similar to glomerular mesangial cells, it is feasible that estradiol inhibits glomerular mesangial cell growth via a similar mechanism, and this possibility was investigated. In human glomerular mesangail cells, estradiol concentration dependently (1 to 100 nmol/L) inhibited serum-induced proliferation (cell number) and DNA (3[H]-thymidine incorporation) and collagen (3[H]-proline incorporation) synthesis. The inhibitory effects of estradiol were mimicked by 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little affinity for ERs. 2-Hydroxyestradiol and 2-methoxyestradiol were more potent growth inhibitors than estradiol. The inhibitory effects of estradiol were enhanced by CYP450 inducers 3-methylcholanthrene (10 &mgr;mol/L) and phenobarbital (10 &mgr;mol/L) and blocked by the CYP450 inhibitor 1-aminobenzotriazole (10 &mgr;mol/L). The growth inhibitory effects of estradiol were also blocked by quercetin (10 &mgr;mol/L) and OR 486 (10 &mgr;mol/L) inhibitors of catechol-O-methyltransferase (converts catecholestradiols to methoxyestradiols). ICI182780 (ER antagonist with ER binding affinity similar to estradiol) blocked the growth inhibitory effects of estradiol (1 to 100 nmol/L) only at concentrations (>50 &mgr;mol/L) that inhibited estradiol metabolism to catecholestradiols. The growth inhibitory effects of 2-hydroxyestradiol were abrogated by quercetin and OR486 (two structurally dissimilar catechol-O-methyltransferase inhibitors), but not by ICI182780. However, the growth inhibitory effects of 2-methoxyestradiol were unaltered by catechol-O-methyltransferase inhibitors and ICI182780. In conclusion, our findings provide the first evidence that methoxyestradiols mediate the growth inhibitory effects of locally applied estradiol on glomerular mesangial cell growth via an ER-independent mechanism.

[1]  L. Zacharia,et al.  Methoxyestradiols Mediate the Antimitogenic Effects of Locally Applied Estradiol on Cardiac Fibroblast Growth , 2002, Hypertension.

[2]  L. Zacharia,et al.  Catecholamines Abrogate Antimitogenic Effects of 2-Hydroxyestradiol on Human Aortic Vascular Smooth Muscle Cells , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[3]  E. Jackson,et al.  Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms. , 2001, American journal of physiology. Renal physiology.

[4]  E. Jackson,et al.  Effects of Estradiol and Its Metabolites on Glomerular Endothelial Nitric Oxide Synthesis and Mesangial Cell Growth , 2001, Hypertension.

[5]  L. Zacharia,et al.  Increased 2-Methoxyestradiol Production in Human Coronary Versus Aortic Vascular Cells , 2001, Hypertension.

[6]  L. Zacharia,et al.  Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms. , 2000, Biochemical and biophysical research communications.

[7]  S. Silbiger,et al.  Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. , 2000, Journal of the American Society of Nephrology : JASN.

[8]  J. Gustafsson,et al.  Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  S. Silbiger,et al.  Estradiol suppresses mesangial cell type I collagen synthesis via activation of the MAP kinase cascade. , 1999, American journal of physiology. Renal physiology.

[10]  S. Kaakkola,et al.  Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. , 1999, Pharmacological reviews.

[11]  J. Corton,et al.  Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor β. , 1998, Endocrinology.

[12]  A. Conney,et al.  Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis? , 1998, Cancer research.

[13]  H. Abboud,et al.  PI-3-kinase and MAPK regulate mesangial cell proliferation and migration in response to PDGF. , 1997, American journal of physiology. Renal physiology.

[14]  R. Karas,et al.  Estrogen inhibits the vascular injury response in estrogen receptor α-deficient mice , 1997, Nature Medicine.

[15]  S. Silbiger,et al.  Effects of sex hormones on mesangial cell proliferation and collagen synthesis. , 1996, Kidney international.

[16]  S. Safe,et al.  Atypical cytochrome P450 induction profiles in glomerular mesangial cells at the mRNA and enzyme level. Evidence for CYP1A1 and CYP1B1 expression and their involvement in benzo[a]pyrene metabolism. , 1996, Biochemical pharmacology.

[17]  S. Silbiger,et al.  The impact of gender on the progression of chronic renal disease. , 1995, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[18]  B. Mico,et al.  1-Aminobenzotriazole-induced destruction of hepatic and renal cytochromes P450 in male Sprague-Dawley rats. , 1992, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[19]  E. Jackson,et al.  Factors controlling growth and matrix production in vascular smooth muscle and glomerular mesangial cells. , 1997, Current opinion in nephrology and hypertension.

[20]  E. Jackson,et al.  Factors controlling growth and matrix production and matrix production in vascular smooth muscle and glomerular mesangial cell , 1997 .

[21]  C. Martucci,et al.  P450 enzymes of estrogen metabolism. , 1993, Pharmacology & therapeutics.

[22]  B. Middleditch,et al.  Bioflavonoid interaction with rat uterine type II binding sites and cell growth inhibition. , 1988, Journal of steroid biochemistry.