Elsevier

Redox Biology

Volume 46, October 2021, 102115
Redox Biology

Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II–induced hypertension

https://doi.org/10.1016/j.redox.2021.102115Get rights and content
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Highlights

  • Orally administered TMAO aggravates Ang II-induced hypertension. Antibiotics alleviate Ang II-induced hypertension by reducing TMAO generation.

  • High concentrations of TMAO constrict afferent arterioles and mesenteric arteries and increase blood pressure.

  • Low concentrations of TMAO enhance Ang II-induced vasoconstriction and acute pressor response via activating PERK/ROS/CaMKII/PLCβ3/Ca2+ pathway.

Abstract

Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg−1min−1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCβ3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCβ3 impaired the effect of TMAO on Ca2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCβ3 axis.

Keywords

Trimethylamine N-oxide
Angiotensin II
Blood pressure
Afferent arteriole
Calcium

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Shan Jiang, Yongjie Shui and Yu Cui are contributed equally to this work.