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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02854-6

摘要内容如下：

年龄是急性肾损伤（AKI）的主要危险因素，但这种风险的生物学机制在很大程度上是未知的。不确定潜能克隆造血（CHIP）增加了几种与衰老相关的慢性疾病的风险。在这里，我们试图测试芯片是否会增加AKI的风险。在三个以人群为基础的流行病学队列中，我们发现CHIP与急性肾损伤（AKI）发生的更大风险相关，这在需要透析的AKI患者和具有除DNMT3A以外的体细胞基因突变（包括TET2和JAK2突变）的个体中更为明显。孟德尔随机化分析支持CHIP在促进AKI中的因果作用。在AKI患者中，非DNMT3A-CHIP也与损伤的非解决模式相关。为了深入了解其机制，我们评估了TET2-CHIP和JAK2V617F-CHIP在两种AKI小鼠模型中的作用。在两种模型中，CHIP均与更严重的AKI、更严重的肾脏促炎巨噬细胞浸润和更严重的AKI后肾脏纤维化相关。总之，这项工作确立了CHIP作为一种遗传机制，通过肾巨噬细胞介导的异常炎症反应，使AKI后受损的肾功能得到恢复。

英文原文如下：

Abstracts

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A, including mutations in TET2 and JAK2. Mendelian randomization analyses supported a causal role for CHIP in promoting AKI. Non-DNMT3A-CHIP was also associated with a nonresolving pattern of injury in patients with AKI. To gain mechanistic insight, we evaluated the role of Tet2-CHIP and Jak2V617F-CHIP in two mouse models of AKI. In both models, CHIP was associated with more severe AKI, greater renal proinflammatory macrophage infiltration and greater post-AKI kidney fibrosis. In summary, this work establishes CHIP as a genetic mechanism conferring impaired kidney function recovery after AKI via an aberrant inflammatory response mediated by renal macrophages.

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