Estrogen and raloxifene, a selective estrogen receptor modulator, ameliorate renal damage in db/db mice.
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.
Chin
Masami
M
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Isono
Motohide
M
Isshiki
Keiji
K
Araki
Shin-ichi
S
Sugimoto
Toshiro
T
Guo
Baoliang
B
Sato
Haruhisa
H
Haneda
Masakazu
M
Kashiwagi
Atsunori
A
Koya
Daisuke
D
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*
D001786:Blood Glucose; D005353:Fibronectins; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D004958:Estradiol