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Updated: Aug 17, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Estrogen and raloxifene, a selective estrogen receptor modulator, ameliorate renal damage in db/db mice
Masami Chin1, Motohide Isono, Keiji Isshiki
1Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Abstract:
Despite the potentially protective effects of estrogen on bone and cardiovascular tissue as well as against kidney diseases, its effects on diabetic nephropathy are unknown. Here, we examined the therapeutic effectiveness of 17beta-estradiol and raloxifene, a selective estrogen receptor modulator, for preventing functional and histological alterations in the kidneys of db/db mice, a model of type 2 diabetes. In the first experiment, ovariectomized female db/db mice were treated with 17beta-estradiol for 8 weeks. The treatment significantly ameliorated albuminuria, attenuated weight gain, and reduced hyperglycemia in diabetic ovariectomized db/db mice. Histologically, the increases in mesangial area and the accumulation of fibronectin were significantly inhibited by 17beta-estradiol. In the second experiment, mice were administered vehicle or raloxifene hydrochloride (3 mg/kg/day) for 8 weeks. Raloxifene significantly reduced mesangial expansion and fibronectin accumulation in db/db mice, but in contrast to 17beta-estradiol, it failed to affect body weight or hyperglycemia. An in vitro experiment further demonstrated that raloxifene inhibited transforming growth factor beta-1-induced fibronectin transcription and AP-1 activity. Thus, our findings suggest that raloxifene, which lacks the harmful effects of estrogen, is useful for the treatment of diabetic nephropathy.
Insights
Raloxifene effectively treats diabetic nephropathy by reducing kidney damage and fibronectin accumulation in mice. This selective estrogen receptor modulator offers a therapeutic option without estrogen
Area of Science:
- Endocrinology
- Nephrology
- Pharmacology
Background:
- Estrogen's protective effects on bone, cardiovascular, and kidney tissues are known, but its role in diabetic nephropathy remains unclear.
- Diabetic nephropathy is a significant complication of type 2 diabetes, characterized by progressive kidney damage.
- Selective estrogen receptor modulators (SERMs) like raloxifene offer potential therapeutic benefits with fewer side effects than estrogen.
Purpose of the Study:
- To investigate the therapeutic efficacy of 17beta-estradiol and raloxifene in preventing kidney damage in a mouse model of type 2 diabetes.
- To evaluate the effects of these compounds on functional and histological alterations in the kidneys of db/db mice.
Main Methods:
- Ovariectomized db/db mice were treated with 17beta-estradiol for 8 weeks.
- Separate groups of db/db mice received vehicle or raloxifene hydrochloride (3 mg/kg/day) for 8 weeks.
- In vitro studies assessed raloxifene's effect on transforming growth factor beta-1-induced fibronectin transcription and AP-1 activity.
Main Results:
- 17beta-estradiol treatment significantly reduced albuminuria, weight gain, and hyperglycemia, and inhibited mesangial area expansion and fibronectin accumulation.
- Raloxifene significantly decreased mesangial expansion and fibronectin accumulation but did not affect body weight or hyperglycemia.
- In vitro, raloxifene inhibited transforming growth factor beta-1-induced fibronectin transcription and AP-1 activity.
Conclusions:
- Raloxifene demonstrates therapeutic potential for treating diabetic nephropathy by mitigating kidney histological damage.
- Raloxifene offers a promising therapeutic strategy for diabetic nephropathy, lacking the systemic effects of estrogen.
- Selective estrogen receptor modulators like raloxifene warrant further investigation for managing diabetic kidney disease.
