Minocycline Normalizes the Hypertension in Gastrin−/− Mice

Abstract

The advent of cutting edge technology has paved the way for the identification of new players for sodium homeostasis and blood pressure (BP) control. The role of gut microbiome in metabolic disorders has been the subject of a growing number of metagenomic and metabolomic studies. Dysbiosis, or the alteration in the gut microbiota composition and function, affects the development of hypertension. Gut microbiota, comprised of mainly of Firmicutes (F) and Bacteroidetes (B), constantly adapt to lifestyle modifications. An increased F/B is observed in rodent and human hypertension. Minocycline selectively inhibits M1 polarization of macrophages, which results in anti‐inflammatory and anti‐hypertensive effects and normalizes the microbiome ratio and thus, the BP. We reported that the hormone gastrin responds to increased dietary sodium load and promotes the excretion of excess sodium through the interaction of renal dopamine receptors (D1R and D5R), and cholecystokinin B receptor (CCKBR), the so‐called “gastrorenal axis”. Gast−/− mice on a salt‐resistant background develop hypertension while wild‐type littermates have normal BP. Gast−/− mice have negligible gastric acid production, which results in increased bacterial survival and dysbiosis of the gut microbiota. Therefore, we tested the hypothesis that minocycline alleviates the high BP of Gast−/− mice. Gast−/− mice and their wild‐type littermates fed a high salt diet (4% NaCl) were given minocycline (50 mg/kg/day, p.o., 28 days). Results showed that minocycline decreased the high BP of conscious Gast−/− mice both at nighttime (130.7±0.4 vs. 123.2±0.3, P<0.05, Dunn's test, 4/group) and daytime (126.1±0.5 vs. 117.5±0.4 P<0.05), and the nighttime (122.4±0.4 vs. 118.4±0.5 P<0.001, Dunn's test, 4/group), but not the daytime BP of the wild‐type littermates. These results imply that inhibition of M1 macrophages decreases BP. In another set of Gast−/− mice, we tested the effect of doxycycline (43 mg/kg/day, p.o., 28 days) which selectively inhibits M2 polarization of macrophages leading to pro‐inflammatory and pro‐hypertensive effects. Doxycycline decreased the BP of conscious Gast−/− mice at nighttime (134.7±0.7 vs. 123.8±8.0 mm Hg, P<0.05, Dunn's test) and at daytime (120.7±0.6 vs. 113.1±2.8 mm Hg), conceivably by normalizing the dysbiosis expected in the knockout mice. By contrast, doxycycline increased BP in wild‐type littermates at nighttime (97.6±1.2 vs. 110.5±5.1 mm Hg) but not at daytime, which can be explained by the inhibition of the M2 macrophage polarization. Thus, the resultant hypertensive phenotype is influenced by the dynamic interplay among genetics, state of inflammation, and gut microbiota.Support or Funding InformationR01DK039308, R01HL092196, and P01HL074940This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.