期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 313, 期 3, 页码 F781-F795出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00166.2017
关键词
natriuretic peptide receptor A; Npr1 gene disruption; retinoic acid; sodium butyrate; proinflammatory cytokines; renal fibrosis
资金
- National Heart, Lung, and Blood Institute [HL-057531, HL-062147]
- National Institute of General Medical Sciences IDeA Program (COBRE Hypertension Pilot Project)
- National Institute of General Medical Sciences IDeA Program (COBRE Aging Pilot Project)
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-kappa B (NF-kappa B) 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-kappa B (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.
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