MECHANICAL STRETCH INDUCES VASCULAR-PERMEABILITY FACTOR IN HUMAN MESANGIAL CELLS - MECHANISMS OF SIGNAL-TRANSDUCTION

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 mo st powerful promoters of vascular permeability, We studied the effect of stretch on VPF production by human mesangial cells and the intracel lular signaling pathways involved. The application of mechanical stret ch (elongation 10%) for 6 h induced a 2.4-fold increase over central i n the VPF mRNA level (P < 0.05), There was a corresponding 3-fold incr ease in VPF protein level by 12 h (P < 0.001), returning to the baseli ne by 24 h, Stretch-induced VPF secretion was partially prevented both by the protein kinase C (PKC) inhibitor H7 (50 mu M: 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 mu g/ml), herbimycin A (3.4 mu M), and a specific pp60(src) peptide inhibitor (21 mu M) 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 complet ely 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.