Renal Denervation Modulates Hypothalamic Neuroinflammation via P2X7R/PI3K/Akt

BACKGROUND: Hypertension remains the leading global contributor to cardiovascular mortality. Although renal denervation (RDN) has demonstrated efficacy, the central neurobiological mechanisms sustaining its sympathoinhibitory effects remain unclear. We investigated whether RDN modulates the ATP and P2X7R (P2X7 receptor)/PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) signaling axis in the hypothalamic paraventricular nucleus to attenuate neuroinflammation and blood pressure. METHODS: Eight-week-old male spontaneously hypertensive rats were randomly assigned to either sham surgery or RDN (combined physical/chemical ablation; n=8 per group). Systolic blood pressure was longitudinally monitored using tail-cuff plethysmography. Cardiac target-organ injury was assessed using hematoxylin-eosin and Masson's trichrome staining. ATP levels, P2X7R expression, and PI3K/Akt phosphorylation in the paraventricular nucleus were quantified by ELISA, Western blotting, and immunofluorescence. A selective P2X7R antagonist (HY-50697/A-740003) was used for pharmacological validation. RESULTS: <0.0001), downregulated P2X7R protein expression, and suppressed pathological activation of the PI3K/Akt signaling pathway, accompanied by reduced proinflammatory cytokine production. Pharmacological inhibition of P2X7R functionally phenocopied the antihypertensive and central anti-inflammatory effects induced by RDN. CONCLUSIONS: RDN was associated with reduced blood pressure and attenuation of central ATP-related neuroinflammatory signaling, beyond peripheral sympathetic disruption. The ATP/P2X7R/PI3K/Akt axis may represent a candidate pathway linking renal signaling to central sympathetic regulation, warranting further investigation as a potential mechanistic target in resistant hypertension.