The incidence of endstage renal disease due to glomerulosclerosis rises with aging in women, especially in minority populations. Women are relatively protected prior to menopause (F/M ratio =0.5), but after menopause this protection is lost (F/M ratio=1.0). Based on these data, we propose that estrogen deficiency after menopause is an important contributor to the development of progressive glomerulosclerosis, particularly in minority women. Glomerulosclerosis, defined as an excess deposition of extracellular matrix, is due to increased matrix synthesis and/or decreased degradation. Matrix metalloproteinases decrease deposition of matrix in vitro, and are linked to decreased glomerulosclerosis in vivo. We will use in vivo and in vitro mouse models of glomerulosclerosis, and human mesangial cell lines developed in our laboratory, as models of the kidney disease in majority (sclerosis-resistant) and minority (sclerosis-prone) women. We recently found that mesangial cells, the major source of sclerotic tissue in glomeruli, express estrogen receptors and that estrogen increases matrix metalloproteinase-2 (MMP-2) activity. We have additional preliminary data showing that the MMP-2 response to estrogen supplementation is blunted in sclerosis-prone mice. These data linking matrix turnover and estrogen response lead us to propose that estrogen retards glomerulosclerosis due, in part, to its stimulatory effect on matrix metalloproteinase-2 activity. A corollary proposal is that appropriate estrogen replacement would decrease the incidence of endstage renal disease in postmenopausal women. These proposals will be tested by identifying and characterizing estrogen receptor subtypes (ERalpha and ERbeta) and receptor activity in mesangial cells from women and sclerosis-prone and sclerosis-resistant mice, using a reporter construct under the transcriptional control of an estrogen responsive element. Mesangial cell MMP expression will be studied under conditions of estrogen deficiency, supplementation and antiestrogen treatment. The response to estrogen of cis-acting elements in the MMP-2 promoter will be studied in mesangial cells using MMP-2 promoter constructs. In addition, glomerular lesions and glomerular MMPs and collagen mRNA levels will be studied in ovariectomized mice in the presence of estrogen deficiency or supplementation and antiestrogen treatment. These data will provide data as to whether estrogen retards the progression of glomerulosclerosis in postmenopausal women. It may also provide tools to evaluate replacement therapy by estrogen analogues.
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