ACTIVATED MESANGIAL CELLS PRODUCE VASCULAR-PERMEABILITY FACTOR IN EARLY-STAGE MESANGIAL PROLIFERATIVE GLOMERULONEPHRITIS

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine involved in angio genesis, inflammation, and wound healing. Although VPF/VEGF has been r eported to be produced only by glomerular podocytes in glomeruli, it w as found that it is produced by human cultured mesangial cells (MC). T herefore, immunohistochemical analysis (using indirect immunofluoresce nce and in situ hybridization) of VPF/VEGF in normal kidneys (n = 7) a nd biopsy specimens taken from 83 patients with renal diseases, includ ing mesangial proliferative glomerulonephritis (PGN) (n = 58), was per formed to examine whether VPF/VEGF is produced by MC in human PGN. In all of the healthy subjects and all of the patients except those with PGN (disease control subjects), VPF/VEGF protein and mRNA were detecte d mainly in podocytes. However, in some PGN patients, VPF/VEGF protein was demonstrated clearly in MC as well as in podocytes, as some of th e VPF/VEGF was colocalized with alpha-smooth muscle actin, a marker of activated MC, and VPF/VEGF mRNA was expressed by MC and podocytes. Me sangial VPF/VEGF expression level increased significantly in PGN patie nts with early lesions (P < 0.01 versus healthy subjects or disease co ntrol subjects, P < 0.05 versus PGN with later lesions). The time betw een biopsy and disease onset was significantly shorter in PGN patients with than in those without mesangial VPF/VEGF expression (P < 0.01). These findings provide the first evidence that activated MC are a sour ce of VPF/VEGF in human PGN, and indicate that mesangial VPF/VEGF expr ession is characteristic of early lesions of PGN. Because VPF/ VEGF pl ays a pivotal role in tissue repair, MC-produced VPF/VEGF may play pat hophysiologic roles, including promoting recovery from glomerular inju ries, in early-stage PGN.