Decreased adenosine 3′,5′-cyclic monophosphate is a driving factor of P300/SIRT1-mediated histone hyperacetylation in obesity-related hypertension

Background: Obesity is the most significant risk factor associated with primary hypertension. A high-fat diet may lead to obesity-related hypertension, with evidence indicating that individuals with this condition exhibit a diminished adenosine 3′,5′-cyclic monophosphate (cAMP) signaling pathway, although the exact mechanisms remain unclear. This study aimed to investigate the regulatory role of the cAMP signaling pathway in obesity-related hypertension. Methods: A rat model of obesity-related hypertension was established by feeding with a high-fat diet for 16 weeks. Changes in the cAMP signaling pathway and SIRT1 in rat renal tissues were explored using immunohistochemistry, immunofluorescence, and RT-qPCR. The effects and mechanisms of the cAMP signaling pathway on histone 3 lysine 27 acetylation and ACE1 were investigated by intervening in human renal tubular epithelial cells with P300, cAMP activators, SIRT1, cAMP inhibitors, and oleic acid. Results: The cAMP signaling pathway was found to be suppressed in rat renal tissue after feeding a high-fat diet, and a simultaneous decrease in histone deacetylase was observed. Furthermore, we identified that the inhibition of cAMP leads to the reduction of SIRT1 and the induction of P300. In addition, vitro experiments suggested that oleic acid suppressed the cAMP signaling pathway, which subsequently upregulated histone 3 lysine 27 acetylation and angiotensin converting enzyme 1 (ACE1) by increasing the expression of P300 and decreasing the expression of SIRT1. Conclusion: The reduced cAMP signaling pathway in obesity could promote histone 3 lysine 27 acetylation modification and upregulate ACE1 expression by regulating P300 and SIRT1 levels, which may have important implications in the management of obesity-related hypertension.