Estradiol reverses renal injury in Alb/TGF-beta1 transgenic mice.
BACKGROUND
Men with chronic renal disease progress more rapidly to renal failure than do women. Tranforming growth factor-beta (TGF-beta) plays a central role in promoting progressive renal injury, in part due to transcriptional effects mediated by cooperation between Smad proteins and the transcription factor Sp1. Estrogen negatively regulates Sp1 activity and reverses the stimulatory effects of TGF-beta on type IV collagen synthesis and cellular apoptosis in cultured mesangial cells. We hypothesized that the ability of estradiol to reverse the effects of TGF-beta underlies gender dimorphism in the progression of chronic renal disease.


METHODS
We studied Alb/TGF-beta transgenic mice, which overexpress TGF-beta1 and develop proteinuria and progressive glomerulosclerosis. We implanted a sustained-release estradiol pellet or a placebo pellet into control and Alb/TGF-beta transgenic mice at 2 weeks of age. Animals were sacrificed at 5 weeks, at which time urine, blood, and renal tissue were obtained for study.


RESULTS
The sustained-release estradiol pellet achieved a physiologic concentration of estradiol. TGF-beta levels were higher in estradiol-treated mice compared to placebo-treated mice. Proteinuria was reduced in estradiol-treated Alb/TGF-beta mice compared to placebo-treated transgenic mice. Mesangial expansion and closure of capillary loops with enhanced glomerular deposition of type I collagen, type IV collagen, and tissue inhibitor of metalloproteinase (TIMP-2) was observed in glomeruli of placebo-treated transgenic mice. Estrogen therapy reversed these abnormalities.


CONCLUSIONS
Administration of estradiol to Alb/TGF-beta transgenic mice, which overexpress TGF-beta, ameliorated progressive renal injury. The ability of estradiol to reverse the pro-fibrotic effects of TGF-beta, both in vitro and in vivo, may underlie the sexual dimorphism in renal disease progression observed in humans.
Blush
Joel
J
Division of Nephrology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467, USA.
Lei
Jun
J
Ju
Wenjun
W
Silbiger
Sharon
S
Pullman
James
J
Neugarten
Joel
J
D000818:Animals; D017209:Apoptosis; D024042:Collagen Type I / Q000378:metabolism; D003692:Delayed-Action Preparations; D004343:Drug Implants; D004958:Estradiol / Q000494:pharmacology*; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D003692:Delayed-Action Preparations; D004343:Drug Implants; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004958:Estradiol