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

Alessandro Amore, Giovanni Conti, Paola Cirina, Licia Peruzzi, Mirella Alpa, Federico Bussolino, Rosanna Coppo

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)1242-1252
Number of pages11
JournalAmerican Journal of Kidney Diseases
Volume36
Issue number6
Publication statusPublished - 2000

Fingerprint

Mesangial Cells
Vascular Endothelial Growth Factor A
Down-Regulation
Nitric Oxide Synthase
IGA Glomerulonephritis
Nitric Oxide
Reverse Transcriptase Polymerase Chain Reaction
Immunoglobulin A
Messenger RNA
glycosylated IgA
human VEGFA protein
Citrulline
Nitric Oxide Donors
Tritium
Nitroprusside
Sclerosis
Glycosylation
Northern Blotting
Blood Vessels
Culture Media

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

Cite this

Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells. / Amore, Alessandro; Conti, Giovanni; Cirina, Paola; Peruzzi, Licia; Alpa, Mirella; Bussolino, Federico; Coppo, Rosanna.

In: American Journal of Kidney Diseases, Vol. 36, No. 6, 2000, p. 1242-1252.

Research output: Contribution to journalArticle

Amore, Alessandro ; Conti, Giovanni ; Cirina, Paola ; Peruzzi, Licia ; Alpa, Mirella ; Bussolino, Federico ; Coppo, Rosanna. / Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells. In: American Journal of Kidney Diseases. 2000 ; Vol. 36, No. 6. pp. 1242-1252.
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T1 - Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells

AU - Amore, Alessandro

AU - Conti, Giovanni

AU - Cirina, Paola

AU - Peruzzi, Licia

AU - Alpa, Mirella

AU - Bussolino, Federico

AU - Coppo, Rosanna

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

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KW - Desialylated immunoglobulin A (deSia IgA)

KW - Immunoglobulin A (IgA) nephropathy

KW - Mesangial cells (MCs)

KW - Nitric oxide (NO)

KW - Vascular endothelial growth factor (VEGF)

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