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 have 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 were unaffected by high glucose. Non responsiveness of the PKC--GSK3signaling axis suppressed effective re-modeling 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.