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High Ambient Glucose Enhances Sensitivity to TGF-1 via Extracellular Signal—Regulated Kinase and Protein Kinase C Activities in Human Mesangial Cells

Department of Pediatrics, Feinberg School of Medicine, Northwestern University; and Children’s Memorial Institute for Education and Research, Chicago Illinois

Correspondence to Dr. Tomoko Hayashida, Pediatrics W-140, 303 E Chicago Avenue, Ward 12-112, Chicago, IL 60611-3008; Phone: 312-503-2918; Fax: 312-503-1181; E-mail: hayashida{at}northwestern.edu

ABSTRACT. High ambient glucose activates intracellular signaling pathways to induce cytokines such as TGF-1 in the extracellular matrix accumulation of diabetic nephropathy. These same pathways also may directly modulate TGF-1 signaling. R-Smad phosphorylation, association with Smad4, and nuclear accumulation after TGF-1 treatment (1.0 ng/ml) were significantly higher in mesangial cells that were conditioned to 20 mM glucose for 72 h than mesangial cells in 6.5 mM glucose, suggesting that high glucose enhanced responsiveness to TGF-1. Neither TGF-1 bioactivity nor TGF- receptor binding was significantly different between in 6.5 and 20 mM glucose-conditioned cultures. Furthermore, adding a neutralizing anti–TGF-1 antibody during glucose conditioning did not affect the enhanced Smad responsiveness, indicating that enhancement likely did not result from increased TGF- expression. In contrast, a mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK inhibitor, PD98059, completely abrogated the effect of high glucose. Glucose stimulation of ERK was inhibited by the general protein kinase C (PKC) inhibitor calphostin C and by the PKC-specific inhibitor rottlerin, whereas Gö6976, an inhibitor of conventional PKC, had no effect on ERK activity. Specificity of the PKC inhibitors was further verified by PKC and kinase assay. High glucose increased expression of several PKC isozymes, but only PKC showed proportionally increased membrane translocation and kinase activity in cells that were conditioned to 20 mM glucose. Finally, both ERK and PKC inhibition during glucose conditioning abrogated enhanced 1(I) collagen mRNA and promoter induction by TGF-1. Taken together, these data strongly suggest that heightened ERK and PKC activity in high ambient glucose conditions interact with the Smad pathway, leading to enhanced responsiveness to TGF-1 and increased extracellular matrix production in mesangial cells.

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