title: Inhibition of Advanced Glycation End Products (AGEs) Accumulation by Pyridoxamine Modulates Glomerular and Mesangial Cell Estrogen Receptor α Expression in Aged Female Mice.
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.
authors.affiliation: Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Simone
authors.initials: S
authors.lastname: Pereira-Simon
authors.affiliation: Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Rubio
authors.affiliation: Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Xia
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics and Palliative Care, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York, United States of America.
authors.forename: Weijing
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Rhea
authors.initials: R
authors.lastname: Choi
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics and Palliative Care, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York, United States of America.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
authors.affiliation: Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Elliot
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020249:Hormone Replacement Therapy; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D018384:Oxidative Stress; D061251:Primary Cell Culture; D011733:Pyridoxamine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C000593873:Ager protein, mouse; D000975:Antioxidants; D024141:Collagen Type IV; D047628:Estrogen Receptor alpha; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D016212:Transforming Growth Factor beta; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D004958:Estradiol; D011733:Pyridoxamine; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1