Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-β1

Margo P. Cohen, Fuad N. Ziyadeh, Won Hong Soon, Clyde W. Shearman, Elizabeth Hud, Gregory T. Lautenslager, M. Carmen Iglesias-De La Cruz, Sheldon Chen

    Research output: Contribution to journalArticle

    26 Scopus citations

    Abstract

    Background. Glycated albumin has been causally linked to the pathobiology of diabetic renal disease through its ability to stimulate the expression of transforming growth factor-β1 (TGF-β1), activate protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), and promote production of extracellular matrix proteins in cultured glomerular cells. Whether glycated albumin modulates glomerular TGF-β1 expression in vivo is not known. To address this issue, we assessed glomerular TGF-β1 expression and pathology in response to reducing the burden of glycated albumin in vivo. Methods. We measured serum glycated albumin, urine protein, glomerular TGF-β1 expression and morphometry, and collagen IV and fibronectin mRNA in db/m and db/db controls and in db/db mice treated for eight weeks with a synthetic compound that inhibits the condensation of glucose with albumin. Results. In situ hybridization studies showed markedly increased glomerular TGF-β1 mRNA in control db/db mice, which was significantly reduced in db/db mice treated for eight weeks with test compound. The treatment protocol, which normalized serum glycated albumin, concomitantly reduced the elevated protein excretion and the renal overexpression of mRNAs encoding fibronectin and collagen IV, and significantly decreased the mesangial matrix expansion, observed in db/db control animals. Conclusions. These findings, to our knowledge, provide the first evidence that glomerular overexpression of TGF-β1 in diabetes derives at least in part from elevated glycated albumin concentrations, and can be partially suppressed by inhibiting the formation of this glycated protein. The results further suggest that glycated albumin has an important nephropathogenic role in diabetes that is operative, and can be therapeutically addressed, independent of glycemic status.

    Original languageEnglish (US)
    Pages (from-to)2025-2032
    Number of pages8
    JournalKidney International
    Volume61
    Issue number6
    DOIs
    StatePublished - Jan 1 2002

    Keywords

    • Diabetic nephropathy
    • Glycated albumin
    • Hyperglycemia
    • Transforming growth factor-β1
    • db/db mouse

    ASJC Scopus subject areas

    • Nephrology

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    Cohen, M. P., Ziyadeh, F. N., Soon, W. H., Shearman, C. W., Hud, E., Lautenslager, G. T., Iglesias-De La Cruz, M. C., & Chen, S. (2002). Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-β1. Kidney International, 61(6), 2025-2032. https://doi.org/10.1046/j.1523-1755.2002.00352.x