Open AccessMechanical stretch induces vascular permeability factor in human mesangial cells: Mechanisms of signal transduction
Author(s) -
Gabriella Gruden,
Stephen Thomas,
Davina Judith Burt,
Stephen Lane,
Gary Chusney,
Steven H. Sacks,
Giancarlo Viberti
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.22.12112
Subject(s) - protein kinase c , signal transduction , endocrinology , phorbol , medicine , vascular permeability , tyrosine kinase , vascular endothelial growth factor , microbiology and biotechnology , chemistry , secretion , biology , vegf receptors
Hemodynamic abnormalities have been implicated in the pathogenesis of the increased glomerular permeability to protein of diabetic and other glomerulopathies. Vascular permeability factor (VPF) is one of the most powerful promoters of vascular permeability. We studied the effect of stretch on VPF production by human mesangial cells and the intracellular signaling pathways involved. The application of mechanical stretch (elongation 10%) for 6 h induced a 2.4-fold increase over control in the VPF mRNA level (P < 0.05). There was a corresponding 3-fold increase in VPF protein level by 12 h (P < 0.001), returning to the baseline by 24 h. Stretch-induced VPF secretion was partially prevented both by the protein kinase C (PKC) inhibitor H7 (50 μM: 72% inhibition,P < 0.05) and by pretreatment with phorbol ester (phorbol-12-myristate-13 acetate 10− 7 M: 77% inhibition,P < 0.05). A variety of protein tyrosine kinase (PTK) inhibitors, genistein (20 μg/ml), herbimycin A (3.4 μM), and a specific pp60src peptide inhibitor (21 μM) also significantly reduced, but did not entirely prevent, stretch-induced VPF protein secretion (respectively 63%, 80%, and 75% inhibition;P < 0.05 for all). The combination of both PKC and PTK inhibition completely abolished the VPF response to mechanical stretch (100% inhibition,P < 0.05). Stretch induces VPF gene expression and protein secretion in human mesangial cells via PKC- and PTK-dependent mechanisms.