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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Author(s)

    • FURUNO Yumi
    • Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health
    • SAKANASHI Mayuko
    • Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus
    • SABANAI Ken
    • Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health
    • TOYOHIRA Yumiko
    • Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health
    • UENO Susumu
    • Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health
    • WATANABE Seiji
    • Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health
    • TAMURA Masahito
    • Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health
    • MATSUMOTO Tetsuro
    • Department of Urology, School of Medicine, University of Occupational and Environmental Health
    • TANIMOTO Akihide
    • Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences
    • SASAGURI Yasuyuki
    • Department of Pathology, School of Medicine, University of Occupational and Environmental Health
    • SHIMOKAWA Hiroaki
    • Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
    • KUSUHARA Koichi
    • Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health
    • YANAGIHARA Nobuyuki
    • Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health
    • SHIRAHATA Akira
    • Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health
    • TSUTSUI Masato
    • Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health

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<SUP>−/−</SUP> mice. However, the extents of renal lesion formation were markedly and most accelerated in the triply NOS<SUP>−/−</SUP> genotype. UUO also elicited the infiltration of inflammatory macrophages, up-regulation of transforming growth factor (TGF)-<I>β</I>1, and induction of epithelial mesenchymal transition (EMT) in all of the genotypes; however, the extents were again largest by far in the triply NOS<SUP>−/−</SUP> genotype. Importantly, long-term treatment with the angiotensin II type 1 (AT<SUB>1</SUB>)-receptor blocker olmesartan significantly prevented the exacerbation of those renal structural changes after UUO in the triply NOS<SUP>−/−</SUP> genotype, along with amelioration of the macrophage infiltration, TGF-<I>β</I>1 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<SUB>1</SUB>-receptor pathway, demonstrating the critical renoprotective role of all NOSs-derived NO against pathological renal remodeling.

Journal

  • Journal of Pharmacological Sciences

    Journal of Pharmacological Sciences 114(4), 379-389, 2010-12-20

    The Japanese Pharmacological Society

References:  42

Codes

  • NII Article ID (NAID)
    10029890896
  • NII NACSIS-CAT ID (NCID)
    AA11806667
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    13478613
  • NDL Article ID
    10926413
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  NDL  J-STAGE 
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