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 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 microM: 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 microg/ml), herbimycin A (3.4 microM), and a specific pp60(src) peptide inhibitor (21 microM) 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.
Gruden
G
G
Department of Endocrinology, United Medical and Dental Schools, Guy's Hospital, London, SE1 9RT, United Kingdom.
Thomas
S
S
Burt
D
D
Lane
S
S
Chusney
G
G
Sacks
S
S
Viberti
G
G
D002199:Capillary Permeability; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D006439:Hemodynamics; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis*; D010812:Physical Stimulation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C