| First Author | Inada A | Year | 2016 |
| Journal | J Am Soc Nephrol | Volume | 27 |
| Issue | 10 | Pages | 3035-3050 |
| PubMed ID | 26940099 | Mgi Jnum | J:290706 |
| Mgi Id | MGI:6436247 | Doi | 10.1681/ASN.2015070741 |
| Citation | Inada A, et al. (2016) Adjusting the 17beta-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy. J Am Soc Nephrol 27(10):3035-3050 |
| abstractText | Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17beta-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by beta-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 beta-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. |
