Estradiol reverses renal injury in Alb/TGF-β1 transgenic mice

Joel Blush, Jun Lei, Wenjun Ju, Sharon Silbiger, James M. Pullman, Joel Neugarten

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2148-2154
Number of pages7
JournalKidney International
Volume66
Issue number6
DOIs
StatePublished - Dec 2004

Fingerprint

Transgenic Mice
Estradiol
Intercellular Signaling Peptides and Proteins
Kidney
Wounds and Injuries
Placebos
Tissue Inhibitor of Metalloproteinase-2
Collagen Type IV
Chronic Renal Insufficiency
Proteinuria
Estrogens
Smad Proteins
Sp1 Transcription Factor
Mesangial Cells
Sex Characteristics
Renal Insufficiency
Disease Progression
Cultured Cells
Collagen
Urine

Keywords

  • Chronic renal failure
  • Collagen
  • Estradiol
  • Glomerulosclerosis
  • TGF-β1

ASJC Scopus subject areas

  • Nephrology

Cite this

Estradiol reverses renal injury in Alb/TGF-β1 transgenic mice. / Blush, Joel; Lei, Jun; Ju, Wenjun; Silbiger, Sharon; Pullman, James M.; Neugarten, Joel.

In: Kidney International, Vol. 66, No. 6, 12.2004, p. 2148-2154.

Research output: Contribution to journalArticle

Blush, Joel ; Lei, Jun ; Ju, Wenjun ; Silbiger, Sharon ; Pullman, James M. ; Neugarten, Joel. / Estradiol reverses renal injury in Alb/TGF-β1 transgenic mice. In: Kidney International. 2004 ; Vol. 66, No. 6. pp. 2148-2154.
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abstract = "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.",
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AU - Neugarten, Joel

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KW - Glomerulosclerosis

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