Smoking induces glomerulosclerosis in aging estrogen-deficient mice through cross-talk between TGF-β1 and IGF-I signaling pathways

Sharon J. Elliot, Michael Karl, Mariana Berho, Xiaomei Xia, Simone Pereria-Simon, Diego Espinosa-Heidmann, Gary E. Striker

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Smoking is a known risk factor for the progression of chronic kidney diseases. However, its independent contribution to the development of ESRD and the underlying molecular mechanism have not been well elucidated. Although the risk for ESRD is higher in postmenopausal women according to the US Renal Data System, the number of women who smoke is on the rise worldwide. Therefore, the effects of smoking and estrogen status on glomerular function and structure were studied in female B6 mice that were ovariectomized at 3 (young) and 15 mo (aged) of age. The mice received either 17/β-estradiol (E2) replacement or placebo (Pla) and were divided further into groups that were exposed to cigarette smoke (S) and not exposed (NS). Six months of exposure to smoke had no effect on young mice, although aging S/Pla mice exhibited a phenotype of increased albumin excretion associated with a moderately increased glomerular collagen type IV deposition compared with NS/Pla mice. S/Pla mice also had a two-fold increase in glomerular TGF-β, Smad3, and IGF-I receptor mRNA expression compared with the NS group. Mesangial cells that were isolated from S/Pla mice had an increase of IGF-I receptor protein, and IGF-I stimulated a TGF-β reporter construct promoter three-fold. This was blocked by pretreatment with a neutralizing antibody to IGF-, LY294002 (phosphatidylinositol-3 kinase inhibitor) or a dominant negative Smad construct. In addition, Smad3 activation was stimulated by IGF-I and blocked by LY294002, suggesting cross-talk between Smad and the phosphatidylinositol-3 kinase/ AKT pathways. The smoking phenotype was reversed by E2 replacement. In conclusion, smoking induces a phenotype in E2-deficient mice that is characterized by activation and cross-talk between the TGF-β1 and IGF-I signaling pathways.

Original languageEnglish (US)
Pages (from-to)3315-3324
Number of pages10
JournalJournal of the American Society of Nephrology
Issue number12
StatePublished - Dec 2006
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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