Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human kidney samples revealed that hypertension induced mtDNA leakage and promoted the expression of stimulator of interferon genes (STING) in renal epithelial cells. We used angiotensin II (AngII)- and 2K1C-treated mouse kidneys to elucidate the underlying mechanisms. Abnormal renal mtDNA packing caused by AngII promoted STING-dependent production of inflammatory cytokines, macrophage infiltration, and a fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation and immune cell infiltration, attenuating tubule atrophy and extracellular matrix accumulation in vivo and in vitro. These effects delayed CKD progression. Immunoprecipitation assays and liquid chromatography-tandem mass spectrometry showed that STING and ACSL4 were directly combined at the D53 and K412 amino acids of ACSL4. Furthermore, STING induced renal inflammatory response and fibrosis through ACSL4-dependent ferroptosis. Last, inhibition of ACSL4 using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent renal inflammation. These results suggest that targeting the STING/ACSL4 axis might represent a potential strategy for treating hypertension-associated CKD.

高血压是心血管疾病的主要可改变危险因素，通常会导致肾脏终末器官损伤并使慢性肾脏病 （CKD） 复杂化。在本研究中，人肾样本的组织学分析显示，高血压诱导 mtDNA 渗漏并促进肾上皮细胞干扰素基因刺激物 （STING） 的表达。我们使用血管紧张素 II （AngII） 和 2K1C 处理的小鼠肾脏来阐明潜在机制。AngII 引起的异常肾脏 mtDNA 打包促进了炎性细胞因子的 STING 依赖性产生、巨噬细胞浸润和纤维化反应。STING 敲除显着降低核因子-κB 活化和免疫细胞浸润，减轻体内和 体外肾小管萎缩和细胞外基质积累 。这些影响延缓了 CKD 的进展。免疫沉淀测定和液相色谱-串联质谱显示，STING 和 ACSL4 在 ACSL4 的 D53 和 K412 氨基酸处直接结合。此外，STING 通过 ACSL4 依赖性铁死亡诱导肾脏炎症反应和纤维化。最后，使用小干扰 RNA、罗格列酮或 Fer-1 抑制 ACSL4 下调 AngII 诱导的 mtDNA-STING 依赖性肾脏炎症。这些结果表明，靶向 STING/ACSL4 轴可能代表了治疗高血压相关 CKD 的潜在策略。