All ETDs from UAB

Advisory Committee Chair

Jennifer Pollock

Advisory Committee Members

Kelly Hyndman

Carmel McNicholas-Bevensee

David Pollock

Bradley Yoder

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Globally, adult sodium consumption has far exceeded daily intake recommendations, leading to one in ten cardiovascular deaths. Given the rise in hypertension prevalence, uncontrolled hypertension with antihypertensive medication use, and significant associations between high salt intake and high blood pressure, there is a need to better understand the mechanisms involved in hypertension. Nitric oxide synthase 1 (NOS1) is a well-established regulator of fluid and electrolyte balance in the renal collecting duct (CD) with highest activity in the inner medulla (IM). We previously reported that high salt (HS) intake stimulates CD endothelin B receptor (ETBR)/NOS1-dependent generation of NO, thereby inhibiting the epithelial sodium channel (ENaC) and promoting natriuresis. Moreover, a loss of CD NOS1 results in salt-sensitive hypertension, presenting with sodium retention and decreased NO bioavailability in male mice. However, the mechanism underlying HS induced increases of NO production is unclear, and it is unknown if these effects are conserved in female mice. Histone deacetylase 1 (HDAC1) responds to increased fluid flow, as can occur in the CD during HS intake. Hence, this dissertation investigates whether HS intake provokes IM HDAC1 activation of NO production and whether CD NOS1 is critical to maintaining renal homeostasis in female mice. IM from male HS mice expressed 50% more HDAC1 protein, ex vivo blockade of which, with selective HDAC1 inhibitor (MS-275), blunted IM NO production and increased CD ENaC activity. With no change in endothelin-1 (ET-1) peptide or mRNA, we further examined the role of the ET-1/ETBR/NOS1 signaling pathway with chronic ETBR blockade (A-192621), finding that HDAC1 mediated NO production is regulated at the level or downstream of ETBR activation. In HS challenged female mice, deletion of CD NOS1 did not significantly alter NO metabolite excretion, blood pressure, or electrolyte levels. Likewise, genotype differences in ET-1 expression or excretion were not observed, however female CDNOS1KO mice displayed elevated renal vessel AT1R expression compared to flox mice. In summary, HDAC1 is a salt-sensitive enzyme that acutely activates the ETBR/NO pathway, while female mice do not rely on CD NOS1-derived NO production to maintain fluid-electrolyte balance.

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