Complete Disruption of All Nitric Oxide Synthase Genes Causes Markedly Accelerated Renal Lesion Formation Following Unilateral Ureteral Obstruction in Mice In Vivo

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  • Morisada Naoya
    Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan
  • Nomura Masayoshi
    Department of Urology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Nishii Hisae
    Department of Urology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Furuno Yumi
    Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Sakanashi Mayuko
    Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Japan
  • Sabanai Ken
    Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Toyohira Yumiko
    Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Ueno Susumu
    Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Watanabe Seiji
    Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan
  • Tamura Masahito
    Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan
  • Matsumoto Tetsuro
    Department of Urology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Tanimoto Akihide
    Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
  • Sasaguri Yasuyuki
    Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Shimokawa Hiroaki
    Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japan
  • Kusuhara Koichi
    Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan
  • Yanagihara Nobuyuki
    Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan
  • Shirahata Akira
    Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan
  • Tsutsui Masato
    Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Japan

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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 (AT1)-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 AT1-receptor pathway, demonstrating the critical renoprotective role of all NOSs-derived NO against pathological renal remodeling.

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