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.

中文翻译：

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实验性的： TET2 克隆造血通过炎症小体介导的机制易患肾高血压。


背景 高血压发病率随着年龄的增长而增加，是心血管疾病最普遍的危险因素之一。由驱动基因体细胞突变导致的造血系统克隆事件在缺乏明显血液系统疾病的老年人中普遍存在。这种情况被称为年龄相关性克隆性造血 （CH），它是新发现的心血管疾病危险因素。目前尚不清楚老年人 CH 和高血压是否具有因果关系，如果是，机制特征是什么。方法 采用过继骨髓移植小鼠模型检查 Tet2 （ten-11 易位甲基胞嘧啶双加氧酶 2） 克隆性造血与高血压之间的相互作用。结果 在该模型中，Ang II （血管紧张素 II） 的亚减压药剂量早在攻击后 1 天就导致收缩压和舒张压升高。这些条件导致 Tet2 缺陷的促炎单核细胞和骨髓祖细胞群的扩增。Tet2 缺陷促进肾脏 CCL5 （C-C 基序配体 5） 趋化因子表达和巨噬细胞浸润肾脏。与巨噬细胞受累一致，当小鼠接受亚加压剂剂量的 Ang II 治疗时，髓系细胞中的 Tet2 缺陷会促进高血压。造血 Tet2-/- 条件导致钠潴留、肾炎小体激活以及 IL （白细胞介素）-1β 和 IL-18 水平升高。钠转运蛋白的分析表明 NCC （氯化钠同向转运蛋白） 和 NKCC2 （Na+-K+-Cl- 协同转运蛋白 2） 分别在残基 Thr53 和 Ser105 处激活。 施用 NLRP3 （NLR 家族含有 3 个） 炎性小体抑制剂 MCC950 可逆转高血压状态、钠潴留和肾转运蛋白激活。结论 Tet2 介导的 CH 使小鼠对高血压刺激敏感。从机制上讲，由于肾免疫细胞浸润和 NLRP3 炎性小体激活升高，造血 Tet2 缺陷细胞的扩增会促进高血压，从而影响钠潴留。这些数据表明，TET2 CH 携带者患高血压的风险可能较高，免疫调节剂可能有助于治疗该患者群体的高血压。