Catecholamines Block 2-Hydroxyestradiol-Induced Antimitogenesis in Mesangial Cells

Abstract

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 V max of 12.03Ϯ0.32 pmol/10 6 cells/min and an apparent K m of 0.23Ϯ0.04 mol/L. Norepinephrine (10 mol/L) and epinephrine (10 mol/L) significantly inhibited methylation of 0.25 mol/L 2-hydroxyestradiol. Norepinephrine concentration-dependently abrogated the ability of 2-hydroxyestradiol to inhibit 3 H-thymidine incorporation (index of DNA synthesis). In the presence of 5, 10, and 40 mol/L norepinephrine, the inhibitory effect of 0.1 mol/L 2-hydroxyestradiol on 3 H-thymidine incorporation was reduced from 51Ϯ0.7% to 46Ϯ0.4%, 39Ϯ0.3%, and 25Ϯ0.7%, respectively. Similar to DNA synthesis, the inhibitory effects of 2-hydroxyestradiol on cell number and 3 H-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. Key Words: estrogen Ⅲ catecholamines Ⅲ metabolism Ⅲ sympathetic nervous system Ⅲ renal disease Ⅲ glomerulosclerosis E stradiol may have protective effects in the kidney. Compared with age-matched men, the rate of progression of renal disease is lower in premenopausal women. With the onset of menopause and the reduction in 17␤-estradiol (estradiol) synthesis, the progression of renal disease accelerates, and estradiol replacement therapy slows the progression of renal disease. [1][2][3] The mechanisms by which estradiol affords renoprotection are unknown. However, it is known that estradiol inhibits pathological responses (cell proliferation and extracellular matrix production) to vascular injury in part by conversion to 2-hydroxyestradiol, which in turn is methylated by catechol-O-methyl transferase (COMT) to 2-methoxyestradiol. 1,4 -6 Our results suggest that 2-methoxyestradiol importantly contributes to estradiol-induced vascular protection via estrogen receptor (ER)-independent mechanisms. 1,4 -6 Glomerulosclerosis engages mechanisms in glomerular mesangial cells (GMCs)...

A Novel Role for an Endothelial Adrenergic Receptor System in Mediating Catecholestradiol-Induced Proliferation of Uterine Artery Endothelial Cells

“…Normal physiologic circulating catecholamine concentrations are 1-2 nmol/L 20,21,22 and increase dramatically in pathologic cardiovascular conditions and during “fight or flight” stress responses. Hence, we demonstrated that even at a low physiologic concentration (0.1 nmol/L) of both norepinephrine and epinephrine significantly increases P-UAEC, not NP-UAEC, proliferation suggesting that catecholamines indeed may play roles in regulating physiologic angiogenesis during gestation.…”

DPP4 Inhibition, NPY1-36, PYY1-36, SDF-1α, and a Hypertensive Genetic Background Conspire to Augment Cell Proliferation and Collagen Production: Effects That Are Abolished by Low Concentrations of 2-Methoxyestradiol

“…Our previous studies show that 17bestradiol, the major ovarian estrogen, is a potent inhibitor of CF, GMC, and vascular smooth muscle cell proliferation induced by serum. Moreover, these effects of 17b-estradiol are mediated by the conversion of 17b-estradiol to 2ME (Dubey et al, 1998(Dubey et al, , 2000(Dubey et al, , 2003a(Dubey et al, ,b, 2004(Dubey et al, , 2007Xiao et al, 2001;Zacharia et al, 2001Zacharia et al, , 2002Zacharia et al, , 2003Barchiesi et al, 2002Barchiesi et al, , 2006Barchiesi et al, , 2010Dubey and Jackson, 2009;Rigassi et al, 2015), a major nonestrogenic metabolite of 17b-estradiol. Therefore, it is conceivable that because of endogenous 2ME, premenopausal women are resistant to the growthpromoting effects of DPP4 inhibition, NPY 1-36 , SDF-1a, or their combination.…”

Catecholamine Production Along the Nephron

“…Nonetheless, at present, we have not evaluated factors that control the production or release of these hormones by these cells. The findings reported that LLC-PK 1 , MDCK, mIMCD-3 and mIMCD-3(HO) cells in the basal state produce and store catecholamines in an average order of 10 µM (29 pg/mL), concentration in which catecholamines can exert their functions [15,16].…”