Fluid-electrolyte homeostasis requires histone deacetylase function.
Histone deacetylase (HDAC) enzymes regulate transcription through epigenetic modification of chromatin structure, but their specific functions in the kidney remain elusive. We discovered that the human kidney expresses class I HDACs. Kidney medulla-specific inhibition of class I HDACs in the rat during high-salt feeding results in hypertension, polyuria, hypokalemia, and nitric oxide deficiency. Three new inducible murine models were used to determine that HDAC1 and HDAC2 in the kidney epithelium are necessary for maintaining epithelial integrity and maintaining fluid-electrolyte balance during increased dietary sodium intake. Moreover, single-nucleus RNA-sequencing determined that epithelial HDAC1 and HDAC2 are necessary for expression of many sodium or water transporters and channels. In performing a systematic review and meta-analysis of serious adverse events associated with clinical HDAC inhibitor use, we found that HDAC inhibitors increased the odds ratio of experiencing fluid-electrolyte disorders, such as hypokalemia. This study provides insight on the mechanisms of potential serious adverse events with HDAC inhibitors, which may be fatal to critically ill patients. In conclusion, kidney tubular HDACs provide a link between the environment, such as consumption of high-salt diets, and regulation of homeostatic mechanisms to remain in fluid-electrolyte balance.
['Hyndman|Kelly A|KA|', 'Speed|Joshua S|JS|', 'Mendoza|Luciano D|LD|', 'Allan|John M|JM|', 'Colson|Jackson|J|', 'Sedaka|Randee|R|', 'Jin|Chunhua|C|', 'Jung|Hyun Jun|HJ|', 'El-Dahr|Samir|S|', 'Pollock|David M|DM|', 'Pollock|Jennifer S|JS|']
D000818:Animals D001549:Benzamides D001794:Blood Pressure D004573:Electrolytes D005260:Female D056284:Histone Deacetylase 1 D056464:Histone Deacetylase 2 D056572:Histone Deacetylase Inhibitors D006655:Histone Deacetylases D006706:Homeostasis D006801:Humans D007679:Kidney Medulla D008297:Male D009569:Nitric Oxide D011188:Potassium D011725:Pyridines D017207:Rats, Sprague-Dawley D017673:Sodium Chloride, Dietary D014882:Water-Electrolyte Balance
Epigenetics Bioinformatics Cell Biology Epithelial transport of ions and water Nephrology