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Adjusting the 17?-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.

ABSTRACT: Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17?-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by ?-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 ?-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.

SUBMITTER: Inada A

PROVIDER: S-EPMC5042662 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.

Inada Akari A Inada Oogi O Fujii Nobuharu L NL Nagafuchi Seiho S Katsuta Hitoshi H Yasunami Yohichi Y Matsubara Takeshi T Arai Hidenori H Fukatsu Atsushi A Nabeshima Yo-Ichi YI

Journal of the American Society of Nephrology : JASN 20160303 10

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 ...[more]

PMID: 26940099

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Project description:Retinopathy of prematurity (ROP) is a major and leading cause of blindness in premature infants. It has been realized that early treatment for ROP is important. However, all the early treatments of ROP are focusing on peripheral retinal ablation which does not surmount the limit of extinguishing retinal neovascularization and protecting the retinas of children with ROP from the injury of ablation. In this study, we investigated the morphological changes of retina and oxidative stress alterations in the early phase of oxygen-induced retinopathy (OIR) and tested the effects of 17?-estradiol (17?-E2), a nonselective estrogen receptor (ER) agonist, on early phase OIR development. We found that large central capillary-free areas were induced in the retinas of pups exposed to hyperoxia on postnatal day 9 (P9), whereas vascularization was almost complete in the retinas of pups exposed to normoxia at the same age. The concentrations of malondiadehyde (MDA), an end-product of oxidative stress, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a major enzyme producing free radicals, as well as the activity of NADPH oxidase were significantly elevated in the retinas of pups exposed to hyperoxia on P9 and postnatal day 13 (P13) compared to those in age matched pups exposed to normoxia. Treatment with 17?-E2 decreased not only the percentage of the central capillary-free area to total retina area but also the concentrations of MDA and NADPH oxidase as well as the activity of NADPH oxidase in a dose-dependent manner in pups exposed to hyperoxia on p9 and P13. The concentration of VEGF was significantly decreased on P9 but increased on P14 in the retinas of pups exposed to hyperoxia, whereas it was significantly elevated on P9 but decreased on P14 in the retinas of pups treated with 17?-E2. The effect of 17?-E2 could be reversed by the co-treatment with ICI182780, a high affinity estrogen receptor antagonist, which suggested that 17?-E2 might exert its effect on early hyperoxic phase of OIR through estrogen receptor. Our results suggest that treatment with antioxidant drugs at early hyperoxic phase of ROP even before the appearance of retinal neovascularization may be more effective than their application to ROP at late phase, which may abolish the deleterious factors that contribute to retinal neovascularization and promote retinal blood vessels to develop healthily.

Dataset Information

Adjusting the 17?-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.

Publications

Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.

Similar Datasets

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