Vasopressor Administration during Fluid Resuscitation Alters Renal Hemodynamics and Expression of Epigenetic Enzymes of Renal Artery in a Pig Model of Hemorrhagic Shock

Abstract

Renal function is greatly reduced during hemorrhagic shock and resuscitation with vasopressors. Studies suggest chromatin remodeling may be responsible for pathophysiologic responses to shock and resuscitation; however, whether chromatin remodeling underlies renal hemodynamic changes induced by shock and resuscitation with different types of vasopressors is unknown. We aim to examine the effect of vasopressin or norepinephrine infusion during resuscitation on renal hemodynamics, and the role of epigenetic chromatin remodeling enzymes in this response. We hypothesized that renal hemodynamics and expression of chromatin remodeling enzymes of renal artery will be altered in a vasopressor‐dependent manner in a pig model of hemorrhagic shock and resuscitation. Adult pigs were anesthetized and subjected to hemorrhage (n=16), or maintained as non‐hemorrhaged controls (n=6). One hour post‐hemorrhage, pigs were resuscitated with saline up to 2x shed blood volume (SA; n=5), saline plus vasopressin infusion (VP; n=5), or saline plus norepinephrine infusion (NE; n=6). Animals were euthanized 4 to 5 hours post‐hemorrhage. Resuscitation strategy significantly affected hemodynamic parameters within the first hour of treatment. Only VP increased mean arterial pressure compared to SA (71.80±8.60 versus 54.40±5.30 mmHg, p<0.05). Renal vascular resistance of VP and NE, but not SA pigs was elevated compared to non‐hemorrhaged controls (0.20±0.03 and 0.19±0.01, respectively, versus 0.09±0.01 mmHg/ml/min, p<0.05). Gene expression of 84 chromatin remodeling enzymes was tested in renal arteries. SA significantly altered a smaller proportion of chromatin remodeling enzymes than VP or NE (6, 20, and 30 of 84 enzymes, respectively) when compared to non‐hemorrhaged controls. VP and NE upregulated expression of histone deacetylases (HDAC2, HDAC4, HDAC6, HDAC9, HDAC11), SET domain‐containing methyltransferases (SETD7, SETD8, SETDB2, NDS1), methyltransferases (EZH2, PRMT5), and demethylases (KDM5B, KDM6B). Unique to NE, DNA methyltransferases (DNMT1, DNMT3A, DNMT3B) were upregulated. Only SA upregulated expression of SETD4, and NEK6. In all treatment groups, LOC100739818, and RPS6KA3 were upregulated, while SET1B was downregulated. Because we observed renal hemodynamic differences among groups, and HDACs and DNMTs have been shown to regulate nitric oxide synthase 3 (NOS3) expression in vascular cells, we hypothesized that NOS3 gene expression of renal artery will be altered in a vasopressor‐dependent manner. NOS3 expression was not significantly different among resuscitation groups, despite differences in expression of chromatin remodeling enzymes. We are the first to demonstrate that renal hemodynamics and renal artery expression of epigenetic enzymes are regulated differently depending on the type of resuscitation strategy used, thus highlighting the importance of resuscitation strategy in the epigenetic regulation of renal vascular function during treatment of hemorrhagic shock.Support or Funding InformationThe views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the U.S. government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.