Abstract
To gain insight into the glomerular capillary repair mechanisms in immunoglobulin A (IgA) nephropathy, we focused on vascular endothelial growth factor (VEGF-A) and nitric oxide (NO). Because abnormal glycosylation of serum IgA has been shown in IgA nephropathy, we examined whether VEGF-A and NO production by mesangial cells (MCs) could be modulated by aberrantly glycosylated (desialylated or degalactosylated) IgA. VEGF-A and NO synthase (NOS) gene expression were examined by reverse-transcriptase polymerase chain reaction (RT-PCR) or Northern blot analysis, and VEGF-A peptide, by capture enzyme-linked immunosorbent assay and NOS activity as production of tritium ([ 3H]) citrulline from [ 3H] arginine. Semiquantitative densitometric analysis of RT-PCR experiments showed a significant downregulation of VEGF-A messenger RNA (mRNA) in MCs incubated with aberrantly glycosylated IgA. This resulted in decreased release of VEGF-A in culture medium (P <0.01). NOS activity 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, Nω-nitro-L-arginine methyl ester. The NO donor, sodium nitroprusside, induced a bimodal modulation of VEGF; although low concentrations (0.0001 nmol/L) increased VEGF-A synthesis, greater concentrations (1,000 nmol/L) depressed it. In conclusion, we report negative control of VEGF-A synthesis in MCs by aberrantly glycosylated IgA, mediated by enhanced iNOS activity. We speculate that both increased iNOS activity and depressed VEGF-A synthesis might have a role in impairing vascular repair and favor sclerosis in IgA nephropathy. (C) 2000 by the National Kidney Foundation, Inc.
Original language | English |
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Pages (from-to) | 1242-1252 |
Number of pages | 11 |
Journal | American Journal of Kidney Diseases |
Volume | 36 |
Issue number | 6 |
Publication status | Published - 2000 |
Keywords
- Abnormally glycosylated immunoglobulin A (IgA)
- Degalactosylated immunoglobulin A (deGal IgA)
- Desialylated immunoglobulin A (deSia IgA)
- Immunoglobulin A (IgA) nephropathy
- Mesangial cells (MCs)
- Nitric oxide (NO)
- Vascular endothelial growth factor (VEGF)
ASJC Scopus subject areas
- Nephrology