Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells

To gain insight into the glomerular capillary repair mechanisms in immunogl obulin A (IgA) nephropathy, we focused on vascular endothelial growth facto r (VEGF-A) and nitric oxide (NO). Because abnormal glycosylation of serum I gA has been shown in IgA nephropathy, we examined whether VEGF-A and NO pro duction by mesangial cells (MCs) could be modulated by aberrantly glycosyla ted (desialylated or degalactosylated) IgA. VEGF-A and NO synthase (NOS) ge ne expression were examined by reverse-transcriptase polymerase chain react ion (RT-PCR) or Northern blot analysis, and VEGF-A peptide, by capture enzy me-linked immunosorbent assay and NOS activity as production of tritium ([H -3]) citrulline from [H-3] arginine. Semiquantitative densitometric analysi s of RT-PCR experiments showed a significant downregulation of VEGF-A messe nger RNA (mRNA) in MCs incubated with aberrantly glycosylated IgA. This res ulted in decreased release of VEGF-A in culture medium (P < 0.01). NOS acti vity and inducible NOS (iNOS) mRNA were enhanced by aberrantly glycosylated IgA (both P < 0.01). No modulation of constitutive NOS mRNA was found. The depression of the VEGF-A production induced by aberrantly glycosylated IgA was mediated by NO because it was completely reversed by the NOS inhibitor , No-nitro-L-arginine methyl ester. The NO donor, sodium nitroprusside, ind uced a bimodal modulation of VEGF; although low concentrations (0.0001 nmol /L) increased VEGF-A synthesis, greater concentrations (1,000 nmol/L) depre ssed it. In conclusion, we report negative control of VEGF-A synthesis in M Cs by aberrantly glycosylated IgA, mediated by enhanced iNOS activity. We s peculate that both increased iNOS activity and depressed VEGF-A synthesis m ight have a role in impairing vascular repair and favor sclerosis in IgA ne phropathy. (C) 2000 by the National Kidney Foundation, Inc.