Type

Journal Article

Authors

Finian Martin
Madeline Murphy
Ronan O'Leary
Laura Thornton
John Crean
Fiona Furlong

Subjects

Biochemistry

Topics
immediate early proteins humans metabolism intercellular signaling peptides and proteins connective tissue growth factor cdc42 gtp binding protein wounds and injuries cytology drug effects signal transduction pathology toxicity chemotaxis stimulation chemical ctgf protein human rna small interfering biosynthesis protein kinase c epsilon diabetic nephropathies pharmacology glycogen synthase kinase 3 glucose blotting western extracellular space glycogen synthase kinase 3 beta glomerular mesangium electrophoresis polyacrylamide gel microscopy fluorescence cells cultured

Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose. (2007)

Abstract 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-zeta-GSK3beta signaling axis. In high ambient glucose basal PKC-zeta and GSK3beta phosphorylation levels are selectively increased and CTGF-stimulated PKC-zeta and GSK3beta 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-zeta-GSK3beta 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-beta activity in human mesangial cells reversed some of the pathological effects of glucose damage in these cells. We show that inhibition of PKC-beta with LY379196 and PKC-beta siRNA reduced basal PKC-zeta and GSK3beta phosphorylation in human mesangial cells exposed to high glucose. CTGF stimulation under these conditions again resulted in PKC-zeta phosphorylation and human mesangial cell migration. Regulation of PKC-zeta by PKC-beta in this instance may establish PKC-zeta as a target for constraining the progression of mesangial cell dysfunction in the pathogenesis of diabetic nephropathy.
Collections Ireland -> University College Dublin -> PubMed

Full list of authors on original publication

Finian Martin, Madeline Murphy, Ronan O'Leary, Laura Thornton, John Crean, Fiona Furlong

Experts in our system

1
Finian Martin
University College Dublin
Total Publications: 81
 
2
Madeline Murphy
University College Dublin
Total Publications: 37
 
3
John Crean
University College Dublin
Total Publications: 23
 
4
Fiona Furlong
University College Dublin
Total Publications: 17