IP-10 and Mig production by glomerular cells in human proliferative glomerulonephritis and regulation by nitric oxide

• Published in: Journal of the American Society of Nephrology 2002, Vol.13 (1), p.53-64
• Main Authors: ROMAGNANI, Paola, LAZZERI, Elena, GALLI, Grazia, SALVADORI, Maurizio, MAGGI, Enrico, SERIO, Mario, LASAGNI, Laura, MAVILIA, Carmelo, BELTRAME, Chiara, FRANCALANCI, Michela, ROTONDI, Mario, ANNUNZIATO, Francesco, MAURENZIG, Lucia, COSMI, Lorenzo
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cells, Cultured; Chemokine CXCL10; Chemokine CXCL9; Chemokines, CXC - antagonists & inhibitors; Chemokines, CXC - biosynthesis; Chemokines, CXC - genetics; Chemokines, CXC - metabolism; Cyclic GMP - physiology; Epithelial Cells - metabolism; Glomerular Mesangium - metabolism; Glomerulonephritis; Humans; Intercellular Signaling Peptides and Proteins; Interferon-gamma - pharmacology; Kidney - metabolism; Kidney Diseases - metabolism; Kidney Glomerulus; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; NF-kappa B - antagonists & inhibitors; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; RNA, Messenger - metabolism; Tissue Distribution; Tumor Necrosis Factor-alpha - pharmacology; Viscera - metabolism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.V13153

High levels of expression of mRNA and protein for the chemokines interferon-gamma (IFN-gamma)-inducible protein of 10 kD (IP-10) (CXCL10) and the monokine induced by IFN-gamma (Mig) (CXCL9) were observed, by using in situ hybridization and immunohistochemical analyses, in kidney biopsy specimens from patients with glomerulonephritis (GN), particularly those with membranoproliferative or crescentic GN, but not in normal kidneys. Double-immunostaining or combined in situ hybridization and immunohistochemical analyses for IP-10, Mig, and proliferating cell nuclear antigen (PCNA) or alpha-smooth muscle actin (alpha-SMA) revealed that IP-10 and Mig production by resident glomerular cells was a selective property of glomeruli in which mesangial cells demonstrated active proliferation. IP-10 and Mig mRNA and protein were also expressed by primary cultures of human mesangial cells and human visceral epithelial cells after stimulation with IFN- gamma or with IFN-gamma plus tumor necrosis factor-alpha (TNF-alpha) (which produced greater stimulation). The induction of IP-10 and Mig mRNA and protein expression by IFN-gamma plus TNF-alpha was strongly inhibited by nitric oxide (NO) donors, such as sodium nitroprusside or S-nitroso-N-acetylpenicillamine, but not by cGMP analogues. Electrophoretic mobility shift assays demonstrated that NO donors repressed IP-10 gene transcription induced by IFN-gamma plus TNF-alpha through the inhibition of NF-kappaB activation. These data demonstrate that resident glomerular cells in kidneys of patients with proliferative GN produce large amounts of IP-10 and Mig, which may play important pathogenic roles in this disease. These data also indicate that the production of IP-10 and Mig by human mesangial cells can be downregulated by NO donors through cGMP-independent inhibition of NF-kappaB activation.