Expression and regulation of estrogen receptors in mesangial cells: Influence on matrix metalloproteinase-9

Diabetic glomerulosclerosis is characterized by the accumulation of extrace llular matrix (ECM) in the mesangium. Estrogens seem to retard whereas estr ogen deficiency seems to accelerate progressive glomerulosclerosis. Thus, m esangial cells (MC) may be a target for estrogens. Estrogen action is media ted via estrogen receptor (ER) subtypes ER alpha and ER beta. Both ER subty pes were expressed in human and mouse MC. Using an estrogen-responsive repo rter construct in transfection assays, it also was demonstrated that the nu clear ER were transcriptionally active. In the presence of 17 beta -estradi ol (E-2; 10(-10) to 10(-8) M), there was a progressive increase in the mRNA levels of both ER alpha (approximately 1.8-fold and approximately 2.7-fold after 24 and 72 h, respectively) and ER beta (approximately 1.3-fold and a pproximately 2.2-fold after 24 and 72 h, respectively). ER alpha protein le vels increased approximately 2.5-fold after 24 h (10(-10) M, E-2) and up to approximately 5.4-fold after 72 h (10(-9) M, E-2). ER beta protein levels increased approximately 2.1-fold in the presence of E-2 (10(-9) M) after 24 h. Thus, estrogens positively regulate the expression of the ER subtypes, thereby maintaining or increasing MC responsiveness to estrogens. Because d iabetic glomerulosclerosis may be due partly to a decrease in ECM degradati on, the effects of estrogens on matrix metalloproteinases (MMP) were studie d. It was found that E-2 (10(-10) to 10(-8) M) increased both MMP-9 mRNA an d MMP-9 activity in MC. This may be an important mechanism by which estroge ns influence ECM turnover and protect against progression of diabetic glome rulosclerosis.