title: ANG II receptor blockade enhances anti-inflammatory macrophages in anti-glomerular basement membrane glomerulonephritis.
abstract: Macrophages are heterogeneous immune cell populations that include classically activated and alternatively activated (M2) macrophages. We examined the anti-inflammatory effect of ANG II type 1 receptor (AT(1)R) blocker (ARB) on glomerular inflammation in a rat model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). The study focused on infiltrating CD8(+) and CD4(+) cells and macrophages, as well as the heterogeneity of intraglomerular macrophages. Wistar-Kyoto rats were treated with high-dose olmesartan (3 mg.kg(-1).day(-1)), low-dose olmesartan (0.3 mg.kg(-1).day(-1)), or vehicle (control) 7 days before induction of anti-GBM GN. Control rats showed mainly CD8(+) cells and ED1(+) macrophages, with a few CD4(+) cells infiltrating the glomeruli. Necrotizing and crescentic glomerular lesions developed by day 7 with the increase of proteinuria. AT(1)R was expressed on CD8(+) and CD4(+) cells and on ED1(+) macrophages. Low-dose ARB had no anti-inflammatory effects in anti-GBM GN. However, high-dose ARB reduced glomerular infiltration of CD8(+) cells and ED1(+) macrophages and suppressed necrotizing and crescentic lesions by days 5 to 7 (P < 0.05). In addition, high-dose ARB reduced the numbers of ED3(+)-activated macrophages, suppressed glomerular TNF-alpha and IFN-gamma production, and downregulated M1-related chemokine and cytokines (monocyte chemoattractant protein type 1, IL-6, and IL-12). High-dose ARB also enhanced ED2(+) M2 macrophages by day 7 with upregulation of glomerular IL-4 and IL-13 and augmented CCL17, IL-1 receptor antagonist, and IL-10. We concluded that high-dose ARB inhibits glomerular inflammation by increasing the numbers of M2 macrophages and upregulation of anti-inflammatory cytokines and by suppressing M1 macrophage development with downregulation of M1-related proinflammatory cytokines.
authors.affiliation: Departmentsof Analytic Human Pathology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Aki
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Yukinari
authors.initials: Y
authors.lastname: Masuda
authors.forename: Naomi
authors.initials: N
authors.lastname: Kuwahara
authors.forename: Takashi
authors.initials: T
authors.lastname: Arai
authors.forename: Arimi
authors.initials: A
authors.lastname: Ishikawa
authors.forename: Emiko
authors.initials: E
authors.lastname: Fujita
authors.forename: Akiko
authors.initials: A
authors.lastname: Mii
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Natori
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Yuh
authors.initials: Y
authors.lastname: Fukuda
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D016207:Cytokines; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan