Fluid-electrolyte homeostasis requires histone deacetylase function

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.

The Role and Mechanism of Histone Deacetylases in Acute Kidney Injury

“…Since then, various HDACis have been investigated for their antifibrotic and anti-inflammatory effects on renal diseases. HDACis have been shown to be effective in treating a variety of kidney diseases in animal models ( Liu and Zhuang, 2015) ; however, due to their adverse reactions, such as hyponatremia, hypokalemia, edema, and changes in blood pressure ( Hyndman et al, 2020) , their application in clinical trials has been limited. This is probably because most of the research in this area is currently being done using pan-HDACis or class-specific HDACis.…”

Kidney cell type-specific changes in the chromatin and transcriptome landscapes following epithelial Hdac1 and Hdac2 knockdown

“…All animal use and welfare adhered to the NIH Guide for the Care and Use of Laboratory Animals following a protocol reviewed and approved by the Institutional Laboratory Animal Care and Use Committees of the University of Alabama at Birmingham (UAB). Our in house colony of inducible, kidney epithelial Hdac1/Hdac2 knock down mice (Hdac1 Fl/Fl ;Hdac2 Fl/Fl ; doxycycline-inducible Pax8-reverse tetracycline transactivator (rtTA) and bicistronic Cre (LC-1) hemizygous positive) and littermate controls were used and the genotyping protocol and confirmation of knockdown was previously published (15). The littermate control animal genotype was Hdac1 Fl/Fl ;Hdac2 Fl/Fl ,: LC-1 hemizygous but Pax8-rtTA negative.…”

“…Nuclei were isolated from half of a kidney for each group: male control, male KO, female control, and female KO. In 2019, the nuclei were isolated for the snRNA-seq experiment and the details were published in Hyndman et al (15). In 2020, nuclei were isolated from the other half of the kidney from the same mice following the protocol of Muto et al (2) for the snATAC-seq experiment.…”

“…Our snRNA-seq libraries are available at the National Center for Biotechnology Information Gene Expression Ombnibus (GEO) under accession GSE148354. This dataset was originally analyzed with R package Seurat v3.0 and the data were normalized using the SCTransform function (15). In this current study, we reanalyzed the 25,075 high quality nuclei with the LogNormalization and Harmony batch correction (17) functions RunHarmony using Seurat v4.0.2.…”

“…Patients take HDAC inhibitors to treat hematological malignancies and neurological disorders (11). Chronic HDAC inhibitor usage results in an increase odds ratio of experiencing a severe fluid-electrolyte disorder (15) and this can be explained in part by inhibition of HDAC1 and HDAC2 activity in the kidney resulting in a down regulation of salt and water transporters/channels (15). What is unknown is whether these kidney transcriptome differences are due to significant changes in the chromatin structure of these genes or other mechanisms that affect gene expression.…”