实验性 TET2 克隆造血通过炎症体介导的机制易导致肾性高血压

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Circulation research Pub Date : 2024-10-11 Epub Date: 2024-09-05 DOI:10.1161/CIRCRESAHA.124.324492
Ariel H Polizio, Lucila Marino, Kyung-Duk Min, Yoshimitsu Yura, Luca Rolauer, Jesse D Cochran, Megan A Evans, Eunbee Park, Heather Doviak, Emiri Miura-Yura, Miranda E Good, Abigail G Wolpe, Maria Grandoch, Brant E Isakson, Kenneth Walsh
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引用次数: 0

摘要

背景:高血压发病率随年龄增长而增加,是心血管疾病最普遍的危险因素之一。在没有明显血液病的老年人中,由于驱动基因的体细胞突变而导致的造血系统克隆事件非常普遍。这种情况被称为与年龄相关的克隆性造血(CH),是一种新近被确认的心血管疾病风险因素。目前尚不清楚老年克隆性造血和高血压是否有因果关系,如果有,其机理特征是什么:方法和结果:我们采用了一种小鼠收养性骨髓移植模型来研究 Tet2(十-十一易位甲基胞嘧啶二氧酶 2)CH 与高血压之间的相互作用。在该模型中,亚压剂量的 Ang II(血管紧张素 II)导致收缩压和舒张压升高,最早出现在挑战后 1 天。这些条件导致 Tet2 缺陷的促炎单核细胞和骨髓祖细胞扩增。Tet2缺陷促进了肾脏CCL5趋化因子的表达和巨噬细胞向肾脏的浸润。与巨噬细胞的参与相一致,当小鼠接受亚抑制剂量的 Ang II 治疗时,骨髓细胞中的 Tet2 缺失会促进高血压。造血Tet2-/-条件导致钠潴留、肾脏炎症小体激活以及IL(白细胞介素)-1β和IL-18水平升高。对钠转运体的分析表明,NCC(Na+-Cl- 共转运体)和 NKCC2 分别在 Thr53 和 Ser105 残基处被激活。服用 NLRP3 炎性体抑制剂 MCC950 逆转了高血压状态、钠潴留和肾转运体激活:结论:Tet2 介导的 CH 使小鼠对高血压刺激敏感。从机理上讲,造血Tet2缺陷细胞的扩增会促进肾脏免疫细胞浸润和NLRP3炎性体的激活,从而导致高血压,并对钠潴留产生影响。这些数据表明,TET2 CH携带者罹患高血压的风险可能会升高,免疫调节剂可能有助于治疗这类患者的高血压。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Experimental TET2 Clonal Hematopoiesis Predisposes to Renal Hypertension Through an Inflammasome-Mediated Mechanism.

Background: Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease. Clonal events in the hematopoietic system resulting from somatic mutations in driver genes are prevalent in elderly individuals who lack overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (CH), and it is a newly recognized risk factor for cardiovascular disease. It is not known whether CH and hypertension in the elderly are causally related and, if so, what are the mechanistic features.

Methods: A murine model of adoptive bone marrow transplantation was employed to examine the interplay between Tet2 (ten-eleven translocation methylcytosine dioxygenase 2) clonal hematopoiesis and hypertension.

Results: In this model, a subpressor dose of Ang II (angiotensin II) resulted in elevated systolic and diastolic blood pressure as early as 1 day after challenge. These conditions led to the expansion of Tet2-deficient proinflammatory monocytes and bone marrow progenitor populations. Tet2 deficiency promoted renal CCL5 (C-C motif ligand 5) chemokine expression and macrophage infiltration into the kidney. Consistent with macrophage involvement, Tet2 deficiency in myeloid cells promoted hypertension when mice were treated with a subpressor dose of Ang II. The hematopoietic Tet2-/- condition led to sodium retention, renal inflammasome activation, and elevated levels of IL (interleukin)-1β and IL-18. Analysis of the sodium transporters indicated NCC (sodium-chloride symporter) and NKCC2 (Na+-K+-Cl- cotransporter 2) activation at residues Thr53 and Ser105, respectively. Administration of the NLRP3 (NLR family pyrin domain containing 3) inflammasome inhibitor MCC950 reversed the hypertensive state, sodium retention, and renal transporter activation.

Conclusions: Tet2-mediated CH sensitizes mice to a hypertensive stimulus. Mechanistically, the expansion of hematopoietic Tet2-deficient cells promotes hypertension due to elevated renal immune cell infiltration and activation of the NLRP3 inflammasome, with consequences on sodium retention. These data indicate that carriers of TET2 CH could be at elevated risk for the development of hypertension and that immune modulators could be useful in treating hypertension in this patient population.

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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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