Selective estrogen receptor modulators suppress mesangial cell collagen synthesis.
Estrogen receptor modulators (SERMs) are "designer drugs" that exert estrogen-like actions in some cells but not in others. We examined the effects of the SERMs LY-117018 (an analog of raloxifene) and tamoxifen on mesangial cells synthesis of type I and type IV collagen. We found that LY-117018 and tamoxifen suppressed mesangial cell type IV collagen gene transcription and type IV collagen protein synthesis in a dose-dependent manner, with a potency identical to that of estradiol. Type I collagen synthesis was also suppressed by LY-117018 in a dose-dependent manner with a potency identical to that of estradiol but greater than that of tamoxifen. Genistein, which selectively binds to estrogen receptor-beta in nanomolar concentrations, suppressed type I and type IV collagen synthesis, suggesting that estrogen receptor-beta mediates the effects of estrogen on collagen synthesis. Because matrix accumulation is central to the development of glomerulosclerosis, second-generation SERMs may prove clinically useful in ameliorating progressive renal disease without the adverse effects of estrogen on reproductive tissues.
Neugarten
J
J
Nephrology Division, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467, USA.
Acharya
A
A
Lei
J
J
Silbiger
S
S
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019332:Endothelin-1 / Q000494:pharmacology; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism / Q000502:physiology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation
D019332:Endothelin-1; D047629:Estrogen Receptor beta; D004967:Estrogens; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D000804:Angiotensin II; C025430:LY 117018; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases