Renal Medullary Histone Deacetylase Dependent Regulation of Fluid‐Electrolyte Homeostasis During High Salt Feeding

Abstract

Histone deacetylase enzymes (HDACs) regulate gene transcription through epigenetic modification of chromatin structure. HDAC inhibitors (HDACi) are being examined as anti‐inflammatory and anti‐fibrotic therapies in cardiovascular disease. However, adverse events of HDACi use include hyponatremia, hypokalemia, and hypertension suggesting that HDACs are involved in regulation of fluid‐electrolyte balance. Thus, we sought to define the renal physiology and pathophysiology role of HDACs to understand mechanisms of these potentially fatal side effects. We found that class I HDACs are expressed in the human and rat kidney, and that inner medullary HDAC1 abundance is increased 4‐fold with high salt feeding in normotensive male rats. During high salt loading, inhibition of renal medullary class I HDACs with chronic intramedullary interstitial infusion of MS275 (1 mg/kg/day) resulted in a significant increase in polyuria (vehicle = 34.4 ±2.0 ml/day, MS275 = 49.8 ±5.0 ml/day, n = 5, P = 0.012) and decreased plasma potassium (vehicle = 4.9 ±0.2 mmol/L, MS275 = 3.9 ±0.13 mmol/L, n = 5, P = 0.0046). Furthermore, HDACi led to changes in the homeostatic mechanisms of fluid‐electrolyte balance including renal nitric oxide deficiency (vehicle = 9.6±2.7 mmol NOx/day, MS275 = 3.1±0.66 mmol NOX/day, n = 5, P = 0.033). We generated doxycycline‐inducible, collecting duct specific, HDAC1 and HDAC2 knockout mouse (iCDHDAC12KO). In male iCDHDAC12KO mice on a high salt diet, there was significant polyuria (control = 12.9±1.8 ml/day, KO 26.1±5.6 ml/day, n=4–5, P =0.04) and reduced urinary NOX(control = 0.9±0.2 mmol/day, KO = 0.3±.06 mmol/day, n=4–5, P = 0.04). Our findings point to a mechanism whereby HDAC1 promotes NO synthase expression through epigenetic regulation of chromatin structure at the Nos1and Nos3promoters. Given the promising research of HDACi to treat cardiovascular disease, this study provides insight on the mechanisms of the adverse events, which may be fatal to critically ill patients.Support or Funding InformationNIH NIDDK K01DK105038 and the UAB Pittman Scholarship to KAH, NHLBI HL127178 to JSS, and P01 HL123267 to DMP and JSP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.