Interaction of angiotensin II and mechanical stretch on vascular endothelial growth factor production by human mesangial cells.
The antiproteinuric effect of angiotensin-converting enzyme inhibitors underscores the importance of a hemodynamic injury and the renin-angiotensin system in the proteinuria of various glomerular diseases. Vascular endothelial growth factor (VEGF), a potent promoter of vascular permeability, is induced in mesangial cells by both mechanical stretch and TGF-beta1. This study investigates the effect of TGF-beta blockade, angiotensin II (AngII), and the interaction between AngII and stretch on human mesangial cell VEGF production. Exposure to AngII (1 microM) induced a significant increase in VEGF mRNA and protein levels (1.5+/-0.1 and 1.7+/-0.3, respectively, fold increase over control, P<0.05). The AngII receptor (AT1) antagonist Losartan (10 microM) prevented AngII-induced, but not stretch-induced, VEGF protein secretion (AngII 1.7+/-0.3, AngII + Losartan 1.0+/-0.1, P<0.05; stretch 2.4+/-0.4, stretch + Losartan 2.6+/-0.5). Stretch-induced VEGF production was also unaffected by the addition of an anti-TGF-beta neutralizing antibody (stretch 2.85+/-0.82 versus stretch + anti-TGF-beta 2.84+/-0.01, fold increase over control). Simultaneous exposure to both AngII and stretch for 12 h had an additive effect on VEGF production (AngII 1.6+/-0.1, stretch 2.6+/-0.27, AngII + stretch 3.1+/-0.35). Conversely, preexposure to stretch magnified AngII-induced VEGF protein secretion (unstretched + AngII 1.3+/-0.0, stretched + AngII 1.9+/-0.1, P<0.01) with a parallel 1.5-fold increase in AT1 receptor levels. AngII and stretch can both independently induce VEGF production; in addition, mechanical stretch upregulates the AT1 receptor, enhancing the cellular response to AngII.
Gruden
G
G
Department of Endocrinology, Diabetes and Internal Medicine, GKT School of Medicine, King's College London, Guy's Hospital Campus, United Kingdom.
Thomas
S
S
Burt
D
D
Zhou
W
W
Chusney
G
G
Gnudi
L
L
Viberti
G
G
D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000502:physiology; D005920:Glomerular Mesangium / Q000166:cytology / Q000502:physiology*; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D012016:Reference Values; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000804:Angiotensin II