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This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 292/6/F1691    most recent 00342.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Furlong, F. Articles by Martin, F. Search for Related Content PubMed PubMed Citation Articles by Furlong, F. Articles by Martin, F.

Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose

UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland

Submitted 30 August 2006 ; accepted in final form 22 February 2007

High ambient glucose activates intracellular signaling pathways to induce the expression of extracellular matrix and cytokines such as connective tissue growth factor (CTGF). Cell responses to CTGF in already glucose-stressed cells may act to transform the mesangial cell phenotype leading to the development of glomerulosclerosis. We analyzed cell signaling downstream of CTGF in high glucose-stressed mesangial cells to model signaling in the diabetic milieu. The addition of CTGF to primary human mesangial cells activates cell migration which is associated with a PKC--GSK3 signaling axis. In high ambient glucose basal PKC- and GSK3 phosphorylation levels are selectively increased and CTGF-stimulated PKC- and GSK3 phosphorylation was impaired. These effects were not induced by osmotic changes. CTGF-driven profibrotic cell signaling as determined by p42/44 MAPK and Akt phosphorylation was unaffected by high glucose. Nonresponsiveness of the PKC--GSK3 signaling axis suppressed effective remodeling of the microtubule network necessary to support cell migration. However, interestingly the cells remain plastic: modulation of glucose-induced PKC- activity in human mesangial cells reversed some of the pathological effects of glucose damage in these cells. We show that inhibition of PKC- with LY379196 and PKC- siRNA reduced basal PKC- and GSK3 phosphorylation in human mesangial cells exposed to high glucose. CTGF stimulation under these conditions again resulted in PKC- phosphorylation and human mesangial cell migration. Regulation of PKC- by PKC- in this instance may establish PKC- as a target for constraining the progression of mesangial cell dysfunction in the pathogenesis of diabetic nephropathy.

GSK3; PKC-; migration; diabetic nephropathy