Interaction of angiotensin II and mechanical stretch on vascular endothelial growth factor production by human mesangial cells

Abstract

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-β1. This study investigates the effect of TGF-β blockade, angiotensin II (AngII), and the interaction between AngII and stretch on human mesangial cell VEGF production. Exposure to AngII (1 μM) 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 μM) 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-β neutralizing antibody (stretch 2.85 ± 0.82 versus stretch + anti-TGF-β 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.