Adjusting the 17b-etradiol-to-androgen ratio ameliorates diabetic nephropathy

Akari Inada, Oogi Inada, Nobuharu L. Fujii, Seiho Nagafuchi, Hitoshi Katsuta, Yohichi Yasunami, Takeshi Matsubara, Hidenori Arai, Atsushi Fukatsu, Yo Ichi Nabeshima

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Abstract

Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17b-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by b-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 inmale ICER-Tg mice is rescued by adjusting the androgen-to-E2 ratio to approximate that in normoglycemic female ICER-Tgmice. We treated hyperglycemic male ICER-Tgmice 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 b-cell number, and itmarkedly inhibited DNprogression [namely, E2 reduced glomerulosclerosis, collagen IV 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 or collagen IV 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.

Original languageEnglish
Pages (from-to)3035-3050
Number of pages16
JournalJournal of the American Society of Nephrology
Volume27
Issue number10
DOIs
Publication statusPublished - Jan 1 2016

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Diabetic Nephropathies
Androgens
Transgenic Mice
Albuminuria
Hyperglycemia
Collagen
Orchiectomy
Blood Glucose
Estradiol
Theoretical Models
Cell Count
Hormones
Transplants
Glucose

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Inada, A., Inada, O., Fujii, N. L., Nagafuchi, S., Katsuta, H., Yasunami, Y., ... Nabeshima, Y. I. (2016). Adjusting the 17b-etradiol-to-androgen ratio ameliorates diabetic nephropathy. Journal of the American Society of Nephrology, 27(10), 3035-3050. https://doi.org/10.1681/ASN.2015070741

Adjusting the 17b-etradiol-to-androgen ratio ameliorates diabetic nephropathy. / Inada, Akari; Inada, Oogi; Fujii, Nobuharu L.; Nagafuchi, Seiho; Katsuta, Hitoshi; Yasunami, Yohichi; Matsubara, Takeshi; Arai, Hidenori; Fukatsu, Atsushi; Nabeshima, Yo Ichi.

In: Journal of the American Society of Nephrology, Vol. 27, No. 10, 01.01.2016, p. 3035-3050.

Research output: Contribution to journalArticle

Inada, A, Inada, O, Fujii, NL, Nagafuchi, S, Katsuta, H, Yasunami, Y, Matsubara, T, Arai, H, Fukatsu, A & Nabeshima, YI 2016, 'Adjusting the 17b-etradiol-to-androgen ratio ameliorates diabetic nephropathy', Journal of the American Society of Nephrology, vol. 27, no. 10, pp. 3035-3050. https://doi.org/10.1681/ASN.2015070741
Inada, Akari ; Inada, Oogi ; Fujii, Nobuharu L. ; Nagafuchi, Seiho ; Katsuta, Hitoshi ; Yasunami, Yohichi ; Matsubara, Takeshi ; Arai, Hidenori ; Fukatsu, Atsushi ; Nabeshima, Yo Ichi. / Adjusting the 17b-etradiol-to-androgen ratio ameliorates diabetic nephropathy. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 10. pp. 3035-3050.
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