title: Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.
abstract: Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17β-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by β-cell–specific overexpression of inducible cAMP early repressor (ICER) and found that male but not female ICER-Tg mice exhibit sustained hyperglycemia and develop major clinical and pathologic features of human diabetic nephropathy (DN). Thus, we hypothesized that differences in circulating hormone levels have a key role in determining susceptibility to diabetes. Here, we examined whether DN in male ICER-Tg mice is rescued by adjusting the androgen-to-E2 ratio to approximate that in normoglycemic female ICER-Tg mice. We treated hyperglycemic male ICER-Tg mice with orchiectomy (ORX), E2 pellet implantation, or both. E2 pellet implantation at an early stage of DN with or without ORX caused a rapid drop in blood glucose and a dramatic increase in β-cell number, and it markedly inhibited DN progression [namely, E2 reduced glomerulosclerosis, collagen 4 deposition and albuminuria, and prevented hyperfiltration]. Furthermore, E2 pellet implantation was more effective than ORX alone and induced a remarkable improvement, even when initiated at advanced-stage DN. In contrast, induction of normoglycemia by islet transplant in ICER-Tg mice eliminated albuminuria but was less effective than E2 + ORX in reducing glomerulosclerosis, collagen 4 deposition, and hyperfiltration. These findings indicate that E2 treatment is effective, even after establishment of DN, whereas glucose normalization alone does not improve sclerotic lesions. We propose that E2 intervention is a potential therapeutic option for DN.
authors.affiliation: Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Kobe, Japan; akariinada@lmls-kobe.org afukatsu2@gmail.com.
authors.forename: Akari
authors.initials: A
authors.lastname: Inada
authors.affiliation: Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Kobe, Japan; Diabetes and Genes, Advanced Medical Initiatives and.
authors.forename: Oogi
authors.initials: O
authors.lastname: Inada
authors.affiliation: Health Promotion Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, Japan.
authors.forename: Nobuharu L
authors.initials: NL
authors.lastname: Fujii
authors.affiliation: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Seiho
authors.initials: S
authors.lastname: Nagafuchi
authors.affiliation: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katsuta
authors.affiliation: Islet Institute, Fukuoka University, Fukuoka, Japan.
authors.forename: Yohichi
authors.initials: Y
authors.lastname: Yasunami
authors.affiliation: Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Obu, Japan; and.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Arai
authors.affiliation: Department of Nephrology, Yachiyo Hospital, Anjo, Japan akariinada@lmls-kobe.org afukatsu2@gmail.com.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukatsu
authors.affiliation: Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Yo-Ichi
authors.initials: YI
authors.lastname: Nabeshima
mesh_terms: D000728:Androgens / Q000097:blood*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003928:Diabetic Nephropathies / Q000097:blood* / Q000209:etiology*; D004958:Estradiol / Q000097:blood*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000728:Androgens; D001786:Blood Glucose; D004958:Estradiol
keywords: diabetes; diabetes mellitus; diabetic nephropathy; hyperglycemia; islet beta-cells