title: Susceptibility to T cell-mediated injury in immune complex disease is linked to local activation of renin-angiotensin system: the role of NF-AT pathway.
abstract: FcR provides a critical link between ligands and effector cells in immune complex diseases. Emerging evidence reveals that angiotensin (Ang)II exerts a wide variety of cellular effects and contributes to the pathogenesis of inflammatory diseases. In anti-glomerular basement membrane Ab-induced glomerulonephritis (GN), we have previously noted that FcR-deficient mice (gamma(-/-)) surviving from lethal initial damage still developed mesangial proliferative GN, which was drastically prevented by an AngII type 1 receptor (AT1) blocker. We further examined the mechanisms by which renin-Ang system (RAS) participates in this immune disease. Using bone marrow chimeras between gamma(-/-) and AT1(-/-) mice, we found that glomerular injury in gamma(-/-) mice was associated with CD4(+) T cell infiltration depending on renal AT1-stimulation. Based on findings in cutaneous delayed-type hypersensitivity, we showed that AngII-activated renal resident cells are responsible for the recruitment of effector T cells. We next examined the chemotactic activity of AngII-stimulated mesangial cells, as potential mechanisms coupling RAS and cellular immunity. Chemotactic activity for T cells and Th1-associated chemokine (IFN-gamma-inducible protein-10 and macrophage-inflammatory protein 1alpha) expression was markedly reduced in mesangial cells from AT1(-/-) mice. Moreover, this activity was mainly through calcineurin-dependent NF-AT. Although IFN-gamma-inducible protein-10 was NF-kappaB-dependent, macrophage-inflammatory protein 1alpha was dominantly regulated by NF-AT. Furthermore, AT1-dependent NF-AT activation was observed in injured glomeruli by Southwestern histochemistry. In conclusion, our data indicate that local RAS activation, partly via the local NF-AT pathway, enhances the susceptibility to T cell-mediated injury in anti-glomerular basement membrane Ab-induced GN. This novel mechanism affords a rationale for the use of drugs interfering with RAS in immune renal diseases.
authors.affiliation: Renal and Vascular Laboratory, Fundación Jiménez Díaz, Autónoma University, Avenida de los Reyes Católicos 2, 28040-Madrid, Spain.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Carmen
authors.initials: C
authors.lastname: Gómez-Guerrero
authors.forename: Isao
authors.initials: I
authors.lastname: Shirato
authors.forename: Oscar
authors.initials: O
authors.lastname: López-Franco
authors.forename: Purificación
authors.initials: P
authors.lastname: Hernández-Vargas
authors.forename: Guillermo
authors.initials: G
authors.lastname: Sanjuán
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D019703:Calcineurin / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005920:Glomerular Mesangium / Q000276:immunology / Q000378:metabolism; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007105:Immune Complex Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D012882:Skin Tests; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D018925:Chemokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D017452:Receptors, IgG; D014157:Transcription Factors; D000804:Angiotensin II; D019703:Calcineurin