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. CONCLUSION: 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.
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-betatransgenic 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-betatransgenic 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-betamice 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-betatransgenic 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.
Authors: Qihe Xu; Bruce M Hendry; Malcolm Maden; Huiyan Lu; Yuen Fei Wong; Alexandra C Rankin; Mazhar Noor; Jeffrey B Kopp Journal: Nephron Exp Nephrol Date: 2010-01-21