title: Complete disruption of all nitric oxide synthase genes causes markedly accelerated renal lesion formation following unilateral ureteral obstruction in mice in vivo.
abstract: The role of nitric oxide (NO) derived from all three NO synthases (NOSs) in renal lesion formation remains to be fully elucidated. We addressed this point in mice lacking all NOSs. Renal injury was induced by unilateral ureteral obstruction (UUO). UUO caused significant renal lesion formation (tubular apoptosis, interstitial fibrosis, and glomerulosclerosis) in wild-type, singly, and triply NOS(-/-) mice. However, the extents of renal lesion formation were markedly and most accelerated in the triply NOS(-/-) genotype. UUO also elicited the infiltration of inflammatory macrophages, up-regulation of transforming growth factor (TGF)-β1, and induction of epithelial mesenchymal transition (EMT) in all of the genotypes; however, the extents were again largest by far in the triply NOS(-/-) genotype. Importantly, long-term treatment with the angiotensin II type 1 (AT(1))-receptor blocker olmesartan significantly prevented the exacerbation of those renal structural changes after UUO in the triply NOS(-/-) genotype, along with amelioration of the macrophage infiltration, TGF-β1 levels, and EMT. These results provide the first evidence that the complete disruption of all NOS genes results in markedly accelerated renal lesion formation in response to UUO in mice in vivo through the AT(1)-receptor pathway, demonstrating the critical renoprotective role of all NOSs-derived NO against pathological renal remodeling.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Morisada
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Nomura
authors.forename: Hisae
authors.initials: H
authors.lastname: Nishii
authors.forename: Yumi
authors.initials: Y
authors.lastname: Furuno
authors.forename: Mayuko
authors.initials: M
authors.lastname: Sakanashi
authors.forename: Ken
authors.initials: K
authors.lastname: Sabanai
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.forename: Seiji
authors.initials: S
authors.lastname: Watanabe
authors.forename: Masahito
authors.initials: M
authors.lastname: Tamura
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Kusuhara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.forename: Akira
authors.initials: A
authors.lastname: Shirahata
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005838:Genotype; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D014517:Ureteral Obstruction
chemical_list: D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase