Salt-Responsive Metabolite, β-Hydroxybutyrate, Attenuates Hypertension

Cell Rep. 2018 Oct 16;25(3):677-689.e4. doi: 10.1016/j.celrep.2018.09.058.


Dietary salt reduction and exercise are lifestyle modifications for salt-sensitive hypertensives. While exercise has prominent metabolic effects, salt has an adverse effect on metabolic syndrome, of which hypertension is a hallmark. We hypothesized that dietary salt impacts metabolism in a salt-sensitive model of hypertension. An untargeted metabolomic approach demonstrates lower circulating levels of the ketone body, beta-hydroxybutyrate (βOHB), in high salt-fed hypertensive rats. Despite the high salt intake, specific rescue of βOHB levels by nutritional supplementation of its precursor, 1,3-butanediol, attenuates hypertension and protects kidney function. This beneficial effect of βOHB was likely independent of gut-microbiotal and Th17-mediated effects of salt and instead facilitated by βOHB inhibiting the renal Nlrp3 inflammasome. The juxtaposed effects of dietary salt and exercise on salt-sensitive hypertension, which decrease and increase βOHB respectively, indicate that nutritional supplementation of a precursor of βOHB provides a similar benefit to salt-sensitive hypertension as exercise.

Keywords: Nlrp3; blood pressure; hypertension; inflammasome; inflammation; ketone body; kidney; metabolomics; salt; β-hydroxybutyrate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / administration & dosage
  • 3-Hydroxybutyric Acid / pharmacology*
  • Animals
  • Blood Pressure
  • Flavoring Agents / toxicity
  • Gastrointestinal Microbiome / drug effects*
  • Hypertension / chemically induced
  • Hypertension / metabolism
  • Hypertension / prevention & control*
  • Inflammasomes / drug effects*
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Male
  • Metabolome / drug effects*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Rats
  • Rats, Inbred Dahl
  • Sodium Chloride, Dietary / toxicity*


  • Flavoring Agents
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, rat
  • Sodium Chloride, Dietary
  • 3-Hydroxybutyric Acid