TY - JOUR
T1 - Estradiol reverses renal injury in Alb/TGF-β1 transgenic mice
AU - Blush, Joel
AU - Lei, Jun
AU - Ju, Wenjun
AU - Silbiger, Sharon
AU - Pullman, James
AU - Neugarten, Joel
N1 - Funding Information:
This study was sponsored by a Grant-in-Aid from the American Heart Association/Heritage Affiliate.
PY - 2004/12
Y1 - 2004/12
N2 - Background. Men with chronic renal disease progress more rapidly to renal failure than do women. Tranforming growth factor-β (TGF-β) 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-β 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-β underlies gender dimorphism in the progression of chronic renal disease. Methods. We studied Alb/TGF-β transgenic mice, which overexpress TGF-β1 and develop proteinuria and progressive glomerulosclerosis. We implanted a sustained-release estradiol pellet or a placebo pellet into control and Alb/TGF-β 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-β levels were higher in estradiol-treated mice compared to placebo-treated mice. Proteinuria was reduced in estradiol-treated Alb/TGF-β 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. Conclusion. Administration of estradiol to Alb/TGF-β transgenic mice, which overexpress TGF-β, ameliorated progressive renal injury. The ability of estradiol to reverse the pro-fibrotic effects of TGF-β, both in vitro and in vivo, may underlie the sexual dimorphism in renal disease progression observed in humans.
AB - Background. Men with chronic renal disease progress more rapidly to renal failure than do women. Tranforming growth factor-β (TGF-β) 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-β 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-β underlies gender dimorphism in the progression of chronic renal disease. Methods. We studied Alb/TGF-β transgenic mice, which overexpress TGF-β1 and develop proteinuria and progressive glomerulosclerosis. We implanted a sustained-release estradiol pellet or a placebo pellet into control and Alb/TGF-β 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-β levels were higher in estradiol-treated mice compared to placebo-treated mice. Proteinuria was reduced in estradiol-treated Alb/TGF-β 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. Conclusion. Administration of estradiol to Alb/TGF-β transgenic mice, which overexpress TGF-β, ameliorated progressive renal injury. The ability of estradiol to reverse the pro-fibrotic effects of TGF-β, both in vitro and in vivo, may underlie the sexual dimorphism in renal disease progression observed in humans.
KW - Chronic renal failure
KW - Collagen
KW - Estradiol
KW - Glomerulosclerosis
KW - TGF-β1
UR - http://www.scopus.com/inward/record.url?scp=21644448251&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=21644448251&partnerID=8YFLogxK
U2 - 10.1111/j.1523-1755.2004.66005.x
DO - 10.1111/j.1523-1755.2004.66005.x
M3 - Article
C2 - 15569304
AN - SCOPUS:21644448251
SN - 0085-2538
VL - 66
SP - 2148
EP - 2154
JO - Kidney international
JF - Kidney international
IS - 6
ER -