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High Salt Diet Induces HDAC1‐Dependent Disruption of Nitric Oxide Signaling in the Renal Microvasculature
Author(s) -
Dunaway Luke S,
Cook Anthony K,
Pollock David M,
Hyndman Kelly A,
Inscho Edward W,
Pollock Jennifer S
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.866.6
Subject(s) - hdac1 , nitric oxide , acetylation , chemistry , hdac8 , histone deacetylase 2 , kidney , endocrinology , medicine , lysine , histone h4 , histone deacetylase , histone , biochemistry , amino acid , gene
Our lab previously reported that in cultured endothelial cells, histone deacetylase 1 (HDAC1) mediates reduced endothelial nitric oxide synthase (NOS3)‐derived NO production and decreased lysine acetylation of NOS3. Recently, we also observed that a high salt diet (HS) increases expression of HDAC1 in the kidney. The objectives of this study were: 1) to test the hypothesis that HS increases HDAC1 abundance or activity in intra‐renal resistance arteries, and, 2) to test the hypothesis that HS mediates HDAC1‐dependent loss of NO signaling in the vasculature. We isolated intra‐renal arteries from male Sprague Dawley rats fed either normal salt diet (NS; 0.49% NaCl) or 2 weeks of HS (4.0% NaCl). HDAC activity was increased as detected by a decrease in histone H3 lysine acetylation status (NS: 1.0 ± 0.033 RDU vs HS: 0.56 ± 0.096 RDU, n=3, p<0.05). This change in HDAC activity was not due to changes in abundance of Class I HDACs: HDAC1 (NS: 1.0 ± 0.11 RDU vs HS: 1.19 ± 0.15 RDU, n=5–8, p>0.05), HDAC2 (NS: 1.0 ± 0.25 RDU vs HS: 1.17 ± 0.13 RDU, n=3–5, p>0.05), HDAC3 (NS: 1.0 ± 0.21 RDU vs HS: 0.99 ± 0.13 RDU, n=3–5, p>0.05), and HDAC8 (NS: 1.0 ± 0.07 RDU vs HS: 0.94 ± .07 RDU, n=3–5, p>0.05). To test the second hypothesis, rat afferent arteriolar vasoconstrictor responses to the NOS inhibitor, LNAME, were monitored using the in vitro, blood perfused juxtamedullary nephron preparation. Arterioles from HS fed rats had significantly blunted L‐NAME‐induced vasoconstriction compared to vehicle treated arterioles from NS fed rats (96 ± 2% of Con vs 76 ± 2% of Con for HS vs. NS; respectively, P<0.05); however, HDAC1 inhibition with 300 nM MS‐275 restored the arteriolar constrictor responses in HS rats (79 ± 3% of Con) to be similar to NS fed rats (P>0.05) and to NS rats + MS‐275 (79 ± 1% of Con; P>0.05). These findings support our hypothesis that HDAC1 regulates NO‐dependent signaling in the renal microvasculature. Support or Funding Information Supported by T32 GM 109780‐3 to LSD, K01 DK105038 to KAH, P01 HL069999 to JSP and DMP, and P01 HL136267 to JSP, EWI, and DMP. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .