Salt-responsive Metabolite, beta-hydroxybutyrate, Attenuates Hypertension

Salt-responsive Metabolite, beta-hydroxybutyrate, Attenuates Hypertension
Chakraborty, S1, Galla, S1, Cheng X1, Yeo, J1, Mell, B1, Singh V1, Yeoh BS1, Saha P1, Mathew, AV2, Vijay-Kumar, M1, Joe B*1.

1Program in Physiological Genomics, Microbiome Consortium, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA. 2 Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, MI, USA.

*Corresponding Author: Bina Joe, [e-mail]
Summary
Dietary salt reduction and exercise are lifestyle modifications prescribed for salt-sensitive hypertensives. While exercise is known to have prominent metabolic effects, such effects of lower dietary salt are just emerging. Studies indicate that salt has 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. Untargeted metabolomic profiling of rats with differential salt (NaCl) diets revealed that a high salt-induced increase in blood pressure was associated with lower circulating levels of the ketone body, beta-hydroxybutyrate (βOHB). Specific rescue of the βOHB levels by nutritional supplementation of its precursor, 1,3-butanediol attenuated hypertension and protected kidney disease despite the high salt intake. This beneficial effect of βOHB was observed independent of the gut-microbiotal effects of salt or the Th17-mediated renal effects. Instead, the mechanism for the observed renoprotective effect of βOHB on salt-sensitive hypertension was the βOHB-mediated inhibition of the pro-inflammatory cascade by the Nlrp3 inflammasome. In summary, the juxtaposed effects of dietary salt and exercise on salt-sensitive hypertension, which decrease and increase βOHB respectively, indicates that nutritional supplementation of a precursor of βOHB could be considered to provide a similar benefit to salt-sensitive hypertension as exercise.