Premium
Histone Deacetylase‐1 is Critical for Flow‐mediated Nitric Oxide Production by the Inner Medullary Collecting Duct
Author(s) -
Hyndman Kelly,
Pollock Jennifer
Publication year - 2015
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.29.1_supplement.968.13
Subject(s) - chemistry , nitrite , nitric oxide , hdac1 , sodium nitrite , sodium butyrate , nitric oxide synthase , histone deacetylase , biophysics , biochemistry , endocrinology , medicine , histone , biology , food science , nitrate , organic chemistry , gene
Collecting duct (CD) nitric oxide synthase‐1 (NOS1, nNOS) is critical for maintaining fluid‐electrolyte balance when eating a high sodium diet. During high sodium feeding, there is increased water intake to maintain hydration resulting in an increased urine flow/shear stress (SS) against the epithelium and increased NO production. The mechanism of the flow‐mediated increase in NO is undetermined. We recently reported that histone deacetylase enzyme‐1 (HDAC1) regulated endothelial‐derived NO. We hypothesized that HDAC1 regulates flow‐stimulated inner medullary (IM) NO production. We determined that HDAC1 and NOS1 form a protein‐protein complex in mIMCD3 cells and mouse IM tissue. mIMCD3 cells were subjected to a normal flow (NF, SS= 3 dynes/cm 2 for 1 h) or high flow (HF, 30 dynes/cm 2 for 1h) to mimic urine flow on normal or high salt diets. Cells were either pretreated with vehicle (0.1% DMSO), MS275 (300 nM) to inhibit HDAC1, MS275 (8 μM) to inhibit Class 1 HDACs, or TSA (500 nM) to inhibit Class 1/2 HDACs. Vehicle treated cells had a flow‐dependent increase in nitrite production (static = 278±35, NF = 515±124, HF = 803±140 pmol/mg pr/h, P<0.01). HDAC1 inhibition (300 nM MS275) attenuated the flow‐mediated increase in nitrite in both the NF and HF (113±44 and 223±51 pmol/mg pr/h, respectively) but not static nitrite production. Whereas, inhibition of multiple Class 1/2 HDAC isoforms did not inhibit static or flow‐mediated nitrite production. These data suggest that HDAC1 is a positive regulator of NOS1, while other class 1 and/or class 2 HDAC isoforms may negatively regulate IMCD NO production. In conclusion, HDAC1 is a novel NOS1 interacting protein and critical for IMCD NO production.