Estrogen actions are largely dependent on the intracellular estrogen receptor (ER) levels. During aging the decline of estrogens or ER leads to a loss in antiinflammatory protection and an increase in oxidant stress due to changes in mitochondrial function. Estrogens/ER may also coordinate signaling between the nucleus and mitochondria through ERK activation, which paradoxically decreases ER expression. The changes in ER expression and transcriptional activation that occur with aging as well as the mitochondria-to-nuclear signaling pathways have not been studied in the glomerulus. We found that ER expression and transcriptional activation decreased with age. Whereas ER levels decreased by greater than 90%, serum 17β-estradiol levels decreased by less than 30%, suggesting alternative mechanisms for ER decrease. Because we postulated that this was due in part to age-related oxidant stress, we treated mesangial cells (MCs) with ethidium bromide (EtBr) to deplete mitochondria. EtBr treatment resulted in decreased ERK activation and reactive oxygen species, which were associated with increased ERα expression and transcriptional activation in old MCs. EtBr treatment also decreased apoptosis and caspase-9 protein expression in old MCs. These data suggest that loss of several of the functions of 17β-estradiol during aging could be mainly due to decreased ERα expression, that the ER loss is reversible by reducing reactive oxygen species, and that mitochondrial retrograde signaling plays a role in this regulation.
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