The gut microbiota downregulates renal MAS1 through H3K9bu in high-fat diet-induced obesity-related hypertensive rats

Obesity is a leading cause of primary hypertension in children, and a high-fat intake and the gut microbiota may be involved in the pathogenesis of obesity-related hypertension (OrHTN), but the underlying mechanisms are not fully understood. Here, we show that high-fat diet (HFD) feeding alters the gut microbiota composition in OrHTN rats, resulting in a reduced abundance of the butyrate-producing bacteria Ruminococcus and a subsequent decrease in plasma butyrate levels. Histone 3 lysine 9 butyrylation (H3K9bu) levels decreased in the kidneys of OrHTN rats, which downregulates the expression of the hypertension-related MAS1 gene. Furthermore, sodium butyrate affected H3K9bu modification levels in a concentration-dependent manner, with decreased H3K9bu and downregulated MAS1 expression at low concentrations in human proximal tubular epithelial cells. Our results suggest that a HFD contributes to the development of OrHTN by altering the gut microbiota and its metabolites, leading to the downregulation of H3K9bu and hypertension-related gene expression. Overall design: We first constructed a rat model of obesity-related hypertension induced by high fat diet, investigated the alterations of gut microbiota and plasma metabolites of the hypertensive rats, detected the levels of histone butyrylation modification in the kidneys, and performed ChIP-seq to explore the potential epigenetic mechanism underlying the development of obesity-related hypertension.