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 unde rscores the importance of a hemodynamic injury and the renin-angiotensin sy stem in the proteinuria of various glomerular diseases. Vascular endothelia l growth factor (VEGF), a potent promoter of vascular permeability, is indu ced in mesangial cells by both mechanical stretch and TGF-beta 1. This stud y investigates the effect of TGF-beta blockade, angiotensin II (AngII), and the interaction between AngII and stretch on human mesangial cell VEGF pro duction. Exposure to AngII (1 mu M) induced a significant increase in VEGF mRNA and protein levels (1.5 +/- 0.1 and 1.7 +/- 0.3, respectively, fold in crease over control, P < 0.05). The AngII receptor (AT1) antagonist Losarta n (10 mu M) prevented AngII-induced, but not stretch-induced, VEGF protein secretion (AngII 1.7 +/- 0.3, AngII + Losartan 1.0 +/- 0.1, P < 0.05; stret ch 2.4 +/- 0.4, stretch + Losartan 2.6 +/- 0.5). Stretch-induced VEGF produ ction 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 +/- 0.0 1, fold increase over control). Simultaneous exposure to both AngII and str etch 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, preexposu re 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 indep endently induce VEGF production; in addition, mechanical stretch upregulate s the AT1 receptor, enhancing the cellular response to AngII.