Abstract
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.
Highlights
Maintenance of fluid-electrolyte balance during challenges such as high-salt diets involves integration of endocrine, paracrine, and autocrine factors
Consistent with increased Histone deacetylase (HDAC) activity, there was a significant decrease in inner medullary (IM) histone H3–lysine acetylation after 7 days of high-salt feeding compared with IM from normal salt–fed rats (Figure 1C)
The main finding from this study reveals that kidney epithelial HDACs are critical in regulating fluid-electrolyte balance
Summary
Maintenance of fluid-electrolyte balance during challenges such as high-salt diets involves integration of endocrine, paracrine, and autocrine factors. These physiological changes result in excretion of excess salt and water and prevent volume expansion and the potential for an increase in blood pressure. Disruption in these pathways can lead to salt-sensitive changes in blood pressure, even in normotensive patients [2,3,4,5]. There is a need to elucidate other pathways that are critical for the maintenance of fluid-electrolyte balance
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