2016年10月
Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.
Journal of the American Society of Nephrology : JASN
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- 巻
- 27
- 号
- 10
- 開始ページ
- 3035
- 終了ページ
- 3050
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1681/ASN.2015070741
- 出版者・発行元
- AMER SOC NEPHROLOGY
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.
- リンク情報
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- DOI
- https://doi.org/10.1681/ASN.2015070741
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/26940099
- PubMed Central
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042662
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000384628500015&DestApp=WOS_CPL
- ID情報
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- DOI : 10.1681/ASN.2015070741
- ISSN : 1046-6673
- eISSN : 1533-3450
- PubMed ID : 26940099
- PubMed Central 記事ID : PMC5042662
- Web of Science ID : WOS:000384628500015