title: Angiotensin II type 1 receptor antagonist attenuates lacrimal gland, lung, and liver fibrosis in a murine model of chronic graft-versus-host disease.
abstract: Chronic graft-versus-host disease (cGVHD), a serious complication following allogeneic HSCT (hematopoietic stem cell transplantation), is characterized by systemic fibrosis. The tissue renin-angiotensin system (RAS) is involved in the fibrotic pathogenesis, and an angiotensin II type 1 receptor (AT1R) antagonist can attenuate fibrosis. Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver. This study aimed to determine whether RAS is involved in fibrotic pathogenesis in the lacrimal gland and to assess the effect of an AT1R antagonist on preventing lacrimal gland, lung, and liver fibrosis in cGVHD model mice. We used the B10.D2→BALB/c (H-2(d)) MHC-compatible, multiple minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD. First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). Next, we administered an AT1R antagonist (valsartan; 10 mg/kg) or angiotensin II type 2 receptor (AT2R) antagonist (PD123319; 10 mg/kg) intraperitoneally into cGVHD model mice and assessed the fibrotic change in the lacrimal gland, lung, and liver. We demonstrated that fibroblasts expressed angiotensin II, AT1R, and AT2R, and that the mRNA expression of angiotensinogen was greater in the lacrimal glands of cGVHD model mice than in controls generated by syngeneic-HSCT. The inhibition experiment revealed that fibrosis of the lacrimal gland, lung, and liver was suppressed in mice treated with the AT1R antagonist, but not the AT2R antagonist. We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice. Our findings point to AT1R antagonist as a possible target for therapeutic intervention in cGVHD.
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Yaguchi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Shigeto
authors.initials: S
authors.lastname: Shimmura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kawakita
authors.forename: Shin
authors.initials: S
authors.lastname: Hatou
authors.forename: Shingo
authors.initials: S
authors.lastname: Satofuka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nakamura
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Imada
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Miyashita
authors.forename: Satoru
authors.initials: S
authors.lastname: Yoshida
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yaguchi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Takehiko
authors.initials: T
authors.lastname: Mori
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D005355:Fibrosis / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006650:Histocompatibility Testing; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000276:immunology; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000276:immunology; D012084:Renin-Angiotensin System / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C073402:PD 123319; D000068756:Valsartan; D014633:Valine