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  • Title: High glucose stimulates proliferation and collagen type I synthesis in renal cortical fibroblasts: mediation by autocrine activation of TGF-beta.
    Author: Han DC, Isono M, Hoffman BB, Ziyadeh FN.
    Journal: J Am Soc Nephrol; 1999 Sep; 10(9):1891-9. PubMed ID: 10477140.
    Abstract:
    Renal tubular epithelial cells and interstitial fibroblasts are active participants in tubulointerstitial fibrosis, the best correlate of decreased glomerular filtration in diabetic nephropathy. It was reported previously that high ambient glucose stimulates transforming growth factor-beta (TGF-beta) mRNA and bioactivity, promotes cellular hypertrophy, and increases collagen synthesis in proximal tubular cells. This study evaluates the effects of high glucose and TGF-beta on the behavior of murine renal cortical fibroblasts (TFB) in culture. High glucose (450 mg/dl) significantly increased [3H]-thymidine incorporation (by 60 to 80% after 24 to 72 h) and cell number, without significantly increasing cell death when compared with normal glucose (100 mg/dl). There also was a transient increase in the mRNA of the c-myc and egr-1 early-response genes. Exogenous TGF-beta1 was promitogenic rather than antiproliferative in contrast to other renal cell types. Northern blot analysis demonstrated constitutive expression of TGF-beta1, -beta2, and -beta3 transcripts. Exposure to high glucose increased all three TGF-beta isoforms in a time-dependent manner. High glucose as well as exogenous TGF-beta1 also increased [3H]-proline incorporation, alpha2(I) collagen mRNA, and type I collagen protein (measured by immunoassay). Treatment with a neutralizing pan-selective monoclonal anti-TGF-beta antibody markedly attenuated the stimulation by high ambient glucose of thymidine incorporation, TGF-beta1 mRNA, and type I collagen mRNA and protein levels. It is concluded that high ambient glucose and exogenous TGF-beta1 share similar actions on renal fibroblasts. Moreover, the stimulation of cell proliferation and collagen type I synthesis in these cells by high ambient glucose are mediated by activation of an autocrine TGF-beta system.
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