Abstract
Age-related increases in oxidant stress (OS) play a role in regulation of estrogen receptor (ER) expression in the kidneys. In this study, we establish that in vivo 17β-estradiol (E2) replacement can no longer upregulate glomerular ER expression by 21 months of age in female mice (anestrous). We hypothesized that advanced glycation end product (AGE) accumulation, an important source of oxidant stress, contributes to these glomerular ER expression alterations. We treated 19-month old ovariectomized female mice with pyridoxamine (Pyr), a potent AGE inhibitor, in the presence or absence of E2 replacement. Glomerular ERα mRNA expression was upregulated in mice treated with both Pyr and E2 replacement and TGFβ mRNA expression decreased compared to controls. Histological sections of kidneys demonstrated decreased type IV collagen deposition in mice receiving Pyr and E2 compared to placebo control mice. In addition, anti-AGE defenses Sirtuin1 (SIRT1) and advanced glycation receptor 1 (AGER1) were also upregulated in glomeruli following treatment with Pyr and E2. Mesangial cells isolated from all groups of mice demonstrated similar ERα, SIRT1, and AGER1 expression changes to those of whole glomeruli. To demonstrate that AGE accumulation contributes to the observed age-related changes in the glomeruli of aged female mice, we treated mesangial cells from young female mice with AGE-BSA and found similar downregulation of ERα, SIRT1, and AGER1 expression. These results suggest that inhibition of intracellular AGE accumulation with pyridoxamine may protect glomeruli against age-related oxidant stress by preventing an increase of TGFβ production and by regulation of the estrogen receptor.
Highlights
Normal aging is associated with an increase in oxidant stress in multiple organs including the kidneys [1, 2]
Glomerular ERα mRNA upregulation by 17β-estradiol replacement is lost by anestrous period (21 months of age)
We have previously shown that E2 upregulates glomerular ERα mRNA and protein expression in young mice [28], but during aging there is a steady decline in both [6]
Summary
Normal aging is associated with an increase in oxidant stress in multiple organs including the kidneys [1, 2] This effect is observed in both sexes, young men have higher levels of oxidant stress markers compared with pre-menopausal age-matched women [3, 4]. Advanced glycation end products (AGEs) are a well-known cause of chronic renal oxidant stress and inflammation [7]. Chronic ingestion of excess AGEs is associated with a marked down-regulation of important anti-oxidant defense mechanisms These include Sirtuin 1 (SIRT1), an NAD+-dependent histone deacetylase, advanced glycation receptor 1 (AGER1), and other anti-oxidant systems such as nuclear factor erythroid 2-related factor 2 (Nrf2) [10, 18]. SIRT1 plays a role in preventing NF-kB (nuclear factor kappa-lightchain-enhancer of activated B cells) activation, which may regulate ER expression [20, 21]
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