RCAN1-Mediated Calcineurin Impairment Drives Sympathetic Outflow in Hypertension

作者：Jingjing Zhou, Jian-Ying Shao, Shao-Rui Chen, Zengyou Ye, Hui‐Lin Pan · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.124.325975 · 被引用次数：8 · 研究领域：Signaling Pathways in Disease、Nitric Oxide and Endothelin Effects、Heart Failure Treatment and Management

BACKGROUND: -methyl-D-aspartate receptors). Clinically used calcineurin inhibitors diminish calcineurin activity in the PVN, leading to persistent overactivation of the sympathetic nervous system. In this study, we investigated the role of calcineurin signaling in the PVN in sympathetic overactivity in spontaneously hypertensive rats (SHR), a widely used genetic model for essential hypertension. METHODS: Arterial blood pressure in conscious animals was recorded via radiotelemetry. Protein-protein interactions were assessed using coimmunoprecipitation, and synaptic NMDAR activity was measured using whole-cell patch-clamp recordings. RESULTS: Calcineurin phosphatase activity in the PVN and other forebrain regions was much lower in SHR than in normotensive Wistar-Kyoto rats (WKY). However, systemic treatment with angiotensin II had no significant effect on brain calcineurin activity. Systemic administration of tacrolimus (FK506), a specific calcineurin inhibitor, induced persistent hypertension in WKY but did not affect the already elevated blood pressure in SHR. Also, microinjection of FK506 into the PVN significantly increased renal sympathetic nerve activity and blood pressure in WKY but had no effect on SHR. Furthermore, FK506 treatment increased α2δ-1-NMDAR interactions and synaptic NMDAR activity in spinally projecting PVN neurons in WKY but not in SHR. Blocking NMDARs with memantine or inhibiting α2δ-1 with gabapentin substantially reduced elevated blood pressure in both ...