Friedrich C . Luft and Hermann Haller

Sclerosis and increased matrix expression in diabetes are mediated by glucose-induced transforming growth factor (TGF)1 expression. The intracellular effects of high glucose occur at least in part by way of protein kinase C (PKC). We previously described a role for PKCin glucose-induced permeability. We now investigated the hypothesis that glucose-induced expression of TGF1 and its receptors (TGF-R1 and -R2) are mediated by activation of this PKC isoform. TGF1 and TGF-R expressions were determined in vascular smooth muscle cells (VSMCs) by immunocytochemistry and Western blotting. PKC isoforms were assessed by confocal microscopy. PKC isoforms were inhibited with antisense oligodeoxynucleotides. PKCwas upregulated by overexpression or microinjection. High glucose (20 mmol/L) increased VSMC TGF1 and TGF-R1 expression but not TGF-R2 expression. PKC inhibitors and specific PKCdownregulation by antisense treatment prevented this effect, whereas antisense treatment against PKC, , and had no influence. PKCoverexpression increased TGF1 and TGF-R1 expression but not TGF-R2 expression. PKCmicroinjection into individual VSMCs also increased TGF1 and TGF-R immunofluorescence. Last, VSMCs from PKC–deficient mice did not respond to high glucose compared with VSMCs from wild-type mice. We propose that high glucose–induced TGF1 and TGF-R1 expression is mediated by PKC. Our findings suggest an autocrine feedback mechanism and a possible role for PKCin diabetic vascular disease. (Hypertension. 2003;42:335-341.)