Inhibition of HDAC enhances STAT acetylation, blocks NF-κB, and suppresses the renal inflammation and fibrosis in Npr1 haplotype male mice.

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  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901990 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1466 (Electronic) Linking ISSN: 15221466 NLM ISO Abbreviation: Am J Physiol Renal Physiol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, Md. : American Physiological Society, c1997-
    • Subject Terms:
      Haplotypes*; Anti-Inflammatory Agents/*pharmacology ; Butyric Acid/*pharmacology ; Histone Deacetylase 1/*metabolism ; Histone Deacetylase 2/*metabolism ; Histone Deacetylase Inhibitors/*pharmacology ; Kidney/*drug effects ; Nephritis/*prevention & control ; Receptors, Atrial Natriuretic Factor/*deficiency ; STAT1 Transcription Factor/*metabolism ; Transcription Factor RelA/*metabolism ; Tretinoin/*pharmacology; Acetylation ; Animals ; Blood Pressure/drug effects ; Cytokines/metabolism ; Disease Models, Animal ; Fibrosis ; Genetic Predisposition to Disease ; Inflammation Mediators/metabolism ; Kidney/enzymology ; Kidney/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Nephritis/enzymology ; Nephritis/genetics ; Nephritis/pathology ; Phenotype ; Receptors, Atrial Natriuretic Factor/genetics ; Signal Transduction/drug effects
    • Abstract:
      Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) plays a critical role in the regulation of blood pressure and fluid volume homeostasis. Mice lacking functional Npr1 (coding for GC-A/NPRA) exhibit hypertension and congestive heart failure. However, the underlying mechanisms remain largely less clear. The objective of the present study was to determine the physiological efficacy and impact of all- trans -retinoic acid (ATRA) and sodium butyrate (NaBu) in ameliorating the renal fibrosis, inflammation, and hypertension in Npr1 gene-disrupted haplotype (1-copy; +/-) mice (50% expression levels of NPRA). Both ATRA and NaBu, either alone or in combination, decreased the elevated levels of renal proinflammatory and profibrotic cytokines and lowered blood pressure in Npr1 +/- mice compared with untreated controls. The treatment with ATRA-NaBu facilitated the dissociation of histone deacetylase (HDAC) 1 and 2 from signal transducer and activator of transcription 1 (STAT1) and enhanced its acetylation in the kidneys of Npr1 +/- mice. The acetylated STAT1 formed a complex with nuclear factor-κB (NF-κB) p65, thereby inhibiting its DNA-binding activity and downstream proinflammatory and profibrotic signaling cascades. The present results demonstrate that the treatment of the haplotype Npr1 +/- mice with ATRA-NaBu significantly lowered blood pressure and reduced the renal inflammation and fibrosis involving the interactive roles of HDAC, NF-κB (p65), and STAT1. The current findings will help in developing the molecular therapeutic targets and new treatment strategies for hypertension and renal dysfunction in humans.
      (Copyright © 2017 the American Physiological Society.)
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    • Grant Information:
      P20 GM103629 United States GM NIGMS NIH HHS; R01 HL062147 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: Npr1 gene disruption; natriuretic peptide receptor A; proinflammatory cytokines; renal fibrosis; retinoic acid; sodium butyrate
    • Accession Number:
      0 (Anti-Inflammatory Agents)
      0 (Cytokines)
      0 (Histone Deacetylase Inhibitors)
      0 (Inflammation Mediators)
      0 (Rela protein, mouse)
      0 (STAT1 Transcription Factor)
      0 (Stat1 protein, mouse)
      0 (Transcription Factor RelA)
      107-92-6 (Butyric Acid)
      5688UTC01R (Tretinoin)
      EC 3.5.1.98 (Hdac1 protein, mouse)
      EC 3.5.1.98 (Hdac2 protein, mouse)
      EC 3.5.1.98 (Histone Deacetylase 1)
      EC 3.5.1.98 (Histone Deacetylase 2)
      EC 4.6.1.2 (Receptors, Atrial Natriuretic Factor)
      EC 4.6.1.2 (atrial natriuretic factor receptor A)
    • Publication Date:
      Date Created: 20170602 Date Completed: 20171002 Latest Revision: 20240718
    • Publication Date:
      20240718
    • Accession Number:
      PMC5625105
    • Accession Number:
      10.1152/ajprenal.00166.2017
    • Accession Number:
      28566502