28/05/2025
🧠💥 The renin-angiotensin system (RAS) plays a central role in regulating blood pressure, fluid balance, and electrolytes. It begins with the liver-derived angiotensinogen (AGT), which is cleaved by renin into angiotensin I (Ang I), then converted by ACE into angiotensin II (Ang II)—the primary active peptide. Ang II acts mainly through the AT1a receptor, causing vasoconstriction, sodium retention, and increased sympathetic activity. A counter-regulatory axis, ACE2/Ang-(1–7)/Mas receptor, promotes vasodilation and cardioprotection.
In addition to its systemic effects, RAS operates locally in organs, including the brain. Within the central nervous system (CNS), the brain RAS influences autonomic and cardiovascular regulation, especially in the subfornical organ (SFO) and the paraventricular nucleus (PVN) of the hypothalamus—key centers for blood pressure control.
The DOCA-salt model of hypertension, which mimics human salt-sensitive hypertension, involves DOCA (a synthetic mineralocorticoid) and a high-salt diet, leading to fluid retention and persistent high blood pressure. Importantly, this model also reveals neurogenic mechanisms, especially in the PVN, where excitatory and inhibitory neurons regulate sympathetic output.
The study shows that DOCA-salt hypertension alters the PVN’s neuronal balance by reducing GABAergic (inhibitory) neurons and increasing glutamatergic (excitatory) ones. This shift is partly driven by PRR-positive neurons transitioning into an excitatory phenotype, intensifying sympathetic tone and sustaining hypertension.
Moreover, ATAC-seq analysis indicates that several RAS-related genes (AGT, ACE, PRR, AT1aR, and AT4R) are upregulated in the PVN during hypertension, suggesting that local brain RAS is highly responsive to hypertensive states.
💡 These insights have major therapeutic implications: targeting brain RAS components or restoring inhibitory signaling in the PVN may help reduce sympathetic overactivation and offer novel strategies for treating neurogenic hypertension, especially through molecular and epigenetic approaches.
https://doi.org/10.3390/biom12091169
