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* Renal and Vascular Laboratory, Fundación Jiménez Díaz, Autónoma University, Madrid, Spain;
Discovery Research Laboratory, Tanabe Seiyaku, Osaka, Japan;
Division of Nephrology, Department of Internal Medicine,
Atopy (Allergy) Research Center, and
¶ Department of Immunology, Juntendo University School of Medicine, and
|| Department of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University School of Medicine, Tokyo, Japan
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 (
-/-)
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 -/- and AT1-/-
mice, we found that glomerular injury in -/-
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--inducible
protein-10 and macrophage-inflammatory protein 1
) expression
was markedly reduced in mesangial cells from AT1-/- mice.
Moreover, this activity was mainly through calcineurin-dependent NF-AT.
Although IFN--inducible protein-10 was NF-
B-dependent,
macrophage-inflammatory protein 1 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.
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