TIP60 mediates stress-induced hypertension via promoting glutamatedmPFC-to-vCA1 release.

Hypertension is well-known to be influenced by genetic and environmental factors. Managing stress is one of the non-pharmacologic approaches to treating hypertension. It is, therefore, imperative to unravel the molecular mechanism by which stress conditions influence hypertension. In this study, TIP60 expressions in human blood samples and cell lines, glutamate^{dmPFC-to-vCA1} release, and receptor expressions in the Stress-induced hypertension mice were determined using western blotting, CSF (obtained by microdialysis), and ELISA. The study reports increased protein expressions of TIP60 in the peripheral blood of hypertensive patients and in cell lines representing hypertension. In Chronic restraint stress (CRS) conditions TIP60 expression and vCA1 glutamate release were found to be up-regulated, with high SBP and DSP indicating hypertension was induced. After electrical stimulation at the dmPFC, release of glutamate in the vCA1 increased, indicating that activity within the dmPFC drives the release of glutamate in the vCA1, which was blocked by injecting MG149 (a TIP60 inhibitor) into dmPFC. To further determine whether TIP60 was involved in glutamate release and eventually results in hypertension, MG149 was also injected i.p. alongside CRS modeling. The increased glutamate release, NR2B, and IL-18 expressions as well as the CRS-induced hypertension was therefore reversed by chronic application with MG149. Altogether, these results suggest that TIP60 influences the glutamate^{dmPFC-to-vCA1} release and receptor expressions. This study, therefore, proposes that stressful condition induces increased expression of TIP60 which lead to the transcription of genes that result in conditions that favors glutamate release and receptor expressions hence triggering hypertension.