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

Diabetic glomerulosclerosis is characterized by the accumulation of extracellular matrix (ECM) in the mesangium. Estrogens seem to retard whereas estrogen deficiency seems to accelerate progressive glomerulosclerosis. Thus, mesangial cells (MC) may be a target for estrogens. Estrogen action is mediated via estrogen receptor (ER) subtypes ERalpha and ERbeta. Both ER subtypes were expressed in human and mouse MC. Using an estrogen-responsive reporter construct in transfection assays, it also was demonstrated that the nuclear ER were transcriptionally active. In the presence of 17beta-estradiol (E2; 10(-10) to 10(-8) M), there was a progressive increase in the mRNA levels of both ERalpha (approximately 1.8-fold and approximately 2.7-fold after 24 and 72 h, respectively) and ERbeta (approximately 1.3-fold and approximately 2.2-fold after 24 and 72 h, respectively). ERalpha protein levels increased approximately 2.5-fold after 24 h (10(-10) M, E2) and up to approximately 5.4-fold after 72 h (10(-9) M, E2). ERbeta 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 diabetic glomerulosclerosis may be due partly to a decrease in ECM degradation, the effects of estrogens on matrix metalloproteinases (MMP) were studied. It was found that E2 (10(-10) to 10(-8) M) increased both MMP-9 mRNA and MMP-9 activity in MC. This may be an important mechanism by which estrogens influence ECM turnover and protect against progression of diabetic glomerulosclerosis.