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Angiotensin II Stimulates the Synthesis and Secretion of Vascular Permeability Factor/Vascular Endothelial Growth Factor in Human Mesangial Cells

CINZIA PUPILLI^*, LAURA LASAGNI^*, PAOLA ROMAGNANI^*, FRANCESCA BELLINI^*, MASSIMO MANNELLI^*, NADIA MISCIGLIA^*, CARMELO MAVILIA, UGO VELLEI^*, DONATA VILLARI and MARIO SERIO^*

^* Department of Clinical Physiopathology, Endocrinology Unit, University of Florence, Italy.
Institute of Internal Medicine and Immunoallergology, University of Florence, Italy.
Clinic of Urology, University of Florence, Italy.

Correspondence to Dr. Cinzia Pupilli, Dipartimento di Fisiopatologia Clinica, Unita' di Endocrinologia, Viale Pieraccini 6, 50139 Firenze, Italy. Phone: +39 55 4221816/906; Fax: +39 55 4221848; E-mail: c.pupilli{at}dfc.unifi.it

Abstract. The aim of the present study was to evaluate the role of angiotensin II (AngII) in regulating both the gene expression and secretion of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) in human mesangial cells (HMC) in culture. Densitometric analysis of Northern blot experiments demonstrated that AngII increases VPF/VEGF mRNA in a dose-dependent manner. The levels of VPF/VEGF mRNA in HMC exposed for 3 h to 10 nM, 100 nM, and 1 µM AngII were, respectively, 1.5-, 2.3-, and 1.6-fold higher than control cells (P < 0.05, P < 0.0001, and P < 0.05, respectively). This effect was blocked by the pretreatment with losartan (1 µM) (P < 0.005), a selective antagonist of the AngII AT₁ receptor. Reverse transcription-PCR performed in HMC using oligonucleotide primers specific for all VPF/VEGF mRNA splicing variants detected three bands corresponding to VEGF 189, 165, and 121. Exposure of the cells to 100 nM AngII resulted in an increase of all the mRNA transcripts. Furthermore, in situ hybridization experiments showed that the levels of hybridization signals for VPF/VEGF mRNA resulted consistently higher in HMC exposed for 3 h to AngII (100 nM) than in control cells. The effects of AngII on the secretion of VPF/VEGF peptide in the culture medium of HMC were assessed using an enzyme-linked immunosorbent assay method. When different concentrations of AngII were tested in 3-h stimulation periods, the percentage of increase in the levels of released VPF/VEGF was significantly higher than control cells for AngII concentrations of 100 nM (62 ± 11% mean ± SD, P < 0.0001) and 1 µM (17.3 ± 10.9%, P < 0.01). The pretreatment of HMC with losartan (1 µM) prevented the increase of VPF/VEGF secretion induced by AngII (100 nM) (AngII 54.7 ± 3.9 pg/µg DNA versus AngII + losartan 37.8 ± 3.6 pg/µg DNA, mean ± SD, P < 0.005). VPF/VEGF protein was time dependently released in the culture medium under basal, steady-state conditions. Compared with control cells, AngII (100 nM) caused a significant increase in the levels of released VPF/VEGF after 3 and 6 h (control 33.8 ± 1.7 pg/µg DNA at 3 h, 42.1 ± 1.1 at 6 h, and 117.7 ± 10 at 24 h; AngII 54.7 ± 3.9 at 3 h, P < 0.0001, 61.6 ± 8.7 at 6 h, P < 0.05, and 144.7 ± 22.7 at 24 h, NS; mean ± SD). According to the results obtained from enzyme-linked immunosorbent assay experiments, Western blot analysis showed that the intensity of the 19-kD band corresponding to VPF/VEGF was 1.5-fold higher in AngII (100 nM)-treated HMC than in control cells. Similarly, immunocytochemistry on HMC demonstrated an increase in intracellular VPF/VEGF immunostaining in response to AngII treatment (100 nM) compared with control cells. This study demonstrated that in HMC, AngII augmented the levels of VPF/VEGF gene expression and stimulated the synthesis and secretion of its peptide by activating AT₁ receptors. Through these mechanisms, AngII may affect the functions of endothelial cells during the development of renal diseases involving the glomerulus.

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