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Objective <p>Hypertension remains a global health crisis, with conventional therapies failing in 40% of patients. Renal denervation (RDN) has emerged as a promising therapeutic alternative for resistant hypertension; however, the mechanisms underlying its antihypertensive effects remain unclear. <i>Ifi27l2a</i>, an interferon-stimulated gene, is implicated in neuroinflammatory processes. Therefore, we investigated the hypertensive mechanisms of RDN, focusing on its effects on <i>Ifi27l2a</i> expression.</p> Methods <p>Cells from the single-cell RNA sequencing datasets were analyzed via clustering and cell type identification to delineate microglial populations impacted by RDN. In vivo experiments were conducted to validate changes in <i>Ifi27l2a</i> expression and cyclic GMP-AMP synthase (cGAS)-STING pathway activation. In vitro, siRNA-mediated <i>Ifi27l2a</i> knockdown in BV2 microglia was employed to evaluate its effects on cGAS-STING pathway activation and cytokine release.</p> Results <p>Single-cell RNA sequencing revealed significant <i>Ifi27l2a</i> downregulation in microglia following RDN. In vivo, cGAS-STING signaling was significantly downregulated, as indicated by decreased cGAS, p-STING, and p-IRF3 expression, which correlated with attenuated neuroinflammatory responses. In vitro validation with <i>Ifi27l2a</i>-knockdown BV2 cells demonstrated coordinated downregulation of inflammatory cytokines and attenuated cGAS-STING pathway activity, confirming its regulatory role in neuroinflammation.</p> Conclusions <p>Ifi27l2a is a crucial link between RDN and neuroinflammation resolution, offering a therapeutic target for resistant hypertension.</p>

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Renal denervation alleviates neuroinflammation by suppressing the microglial Ifi27l2a/cGAS-STING signaling axis

  • 期刊论文

  • 发表日期：

    2025年10月3日

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  • Yiting Xu,
  • Xin Shi,
  • Donghuo Gong,
  • Hongjin Chen,
  • Ming Wang,
  • Wenzheng Han

摘要

Objective

Hypertension remains a global health crisis, with conventional therapies failing in 40% of patients. Renal denervation (RDN) has emerged as a promising therapeutic alternative for resistant hypertension; however, the mechanisms underlying its antihypertensive effects remain unclear. Ifi27l2a, an interferon-stimulated gene, is implicated in neuroinflammatory processes. Therefore, we investigated the hypertensive mechanisms of RDN, focusing on its effects on Ifi27l2a expression.

Methods

Cells from the single-cell RNA sequencing datasets were analyzed via clustering and cell type identification to delineate microglial populations impacted by RDN. In vivo experiments were conducted to validate changes in Ifi27l2a expression and cyclic GMP-AMP synthase (cGAS)-STING pathway activation. In vitro, siRNA-mediated Ifi27l2a knockdown in BV2 microglia was employed to evaluate its effects on cGAS-STING pathway activation and cytokine release.

Results

Single-cell RNA sequencing revealed significant Ifi27l2a downregulation in microglia following RDN. In vivo, cGAS-STING signaling was significantly downregulated, as indicated by decreased cGAS, p-STING, and p-IRF3 expression, which correlated with attenuated neuroinflammatory responses. In vitro validation with Ifi27l2a-knockdown BV2 cells demonstrated coordinated downregulation of inflammatory cytokines and attenuated cGAS-STING pathway activity, confirming its regulatory role in neuroinflammation.

Conclusions

Ifi27l2a is a crucial link between RDN and neuroinflammation resolution, offering a therapeutic target for resistant hypertension.