Elevated glucose stimulates TGF-β gene expression and bioactivity in proximal tubule

Abstract

Our previous studies have demonstrated that raising ambient glucose from 100 to 450 mg/dl significantly inhibited the proliferation of mouse renal proximal tubule cells in culture. This effect was demonstrated after a latent period of 24 to 48 hours. Because transforming growth factor-beta (TGF-beta) inhibits cell proliferation in most epithelial cell lines, we hypothesized that the inhibitory effect of high glucose levels on cell proliferation may be mediated by TGF-beta. The present studies were performed to test the hypothesis that TGF-beta is an autocrine cytokine whose activity can be modulated by ambient glucose. Exogenous TGF-beta inhibited [3H]-thymidine incorporation in a dose-dependent fashion and with high affinity (picomolar range), but with slightly lower potency in high versus normal glucose media. Northern analysis of mRNA demonstrated that proximal tubule cells constitutively express TGF-beta 1 transcripts, and that the steady state level of TGF-beta 1 mRNA was, on average, 63% higher in the cells grown for 48 hours in high versus normal glucose media. Furthermore, the conditioned media of cells exposed to 450 mg/dl glucose exhibited endogenous TGF-beta bioactivity as measured by inhibition of cell proliferation. The addition of a rabbit antiporcine TGF-beta neutralizing antibody significantly increased basal thymidine incorporation in high glucose media to levels approaching those of cells grown in normal glucose media. In contrast, the anti-TGF-beta antibody did not have a significant effect on the growth of cells in the normal glucose media.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

“…Further, we show that TGF-␤ was able to reduce the binding/uptake of albumin by IRPT cells. These findings are in agreement with Gekle et al (22) and suggest that TGF-␤, which is upregulated in diabetes by high glucose (8), may play an important role in the manifestation of albuminuria in diabetic nephropathy independently of its prosclerotic effects on the glomerulus. These studies also implicate sT␤RII.Fc as a potential treatment for diabetic nephropathy, as supported by our in vivo studies carried out in the well-characterized STZ model of type 1 diabetes.…”

“…Transforming growth factor-␤ (TGF-␤) plays an important role in the onset and progression of diabetic nephropathy and may be directly upregulated in diabetes through high blood glucose levels (8). A number of studies have shown that TGF-␤ is an important factor in diabetic nephropathy progression through the use of knockout (KO) mouse models for the TGF-␤ type II receptor (9) (which binds TGF-␤1) and TGF-␤ blocking antibodies (10 -12).…”

Hyperglycemia‐induced TGFβ and fibronectin expression in embryonic mouse heart

“…Cultured rodent and human mesangial cells exposed to 450 -540 mg/dl glucose demonstrate increased TGF␤1 secretion, bioactivity, and mRNA expression (Wahab et al, 1996;Hoffman et al, 1998;Oh et al, 1998). A similar up-regulation of TGF␤1 is produced in cultured renal tubule cells (Rocco et al, 1992) and mesothelial cells exposed to hyperglycemia (Ha et al, 2001) and in the kidneys of human diabetics (Chen et al, 2001).…”

Glucose-Induced TGF-β1 and TGF-β Receptor-1 Expression in Vascular Smooth Muscle Cells Is Mediated by Protein Kinase C-α

“…3,4 The possible importance of TGF-␤1 in diabetic nephropathy has been demonstrated in vitro by glucose-induced upregulation of this cytokine in different cell types. [5][6][7][8][9][10][11][12][13] Increased TGF-␤1 expression has also been demonstrated in diabetic animal models and human patients. 14,15 TGF-␤ binds specific serine/threonine kinase type I and type II receptors.…”