Sexual Dimorphic Role of CD14 (Cluster of Differentiation 14) in Salt-Sensitive Hypertension and Renal Injury
Sexual Dimorphic Role of CD14 (Cluster of Differentiation 14) in Salt-Sensitive Hypertension and Renal Injury
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DOI：
10.1161/hypertensionaha.120.14928
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发表时间：
2021-01-01
期刊：
影响因子：
8.3
通讯作者：
Mattson，David L.
中科院分区：
文献类型：
--
作者：
Fehrenbach，Daniel J.;Abais-Battad，Justine M.;Mattson，David L.
在动物和人类中的基因组序列和基因表达关联研究已经鉴定了可能在各种疾病的发病机制中不可或缺的基因。CD 14（分化簇14）--一种参与先天免疫系统激活的细胞表面蛋白--就是这样一种与心血管和高血压疾病相关的基因。我们以前表明，该基因在Dahl盐敏感动物的肾脏巨噬细胞中上调，这些动物喂食高盐饮食;在这里，我们测试了CD 14有助于盐敏感性高血压中观察到的压力升高和肾损伤的假设。使用CRISPR/Cas9（规律间隔短回文重复序列/规律间隔短回文重复序列相关9），我们在Dahl SS（SS/JrHSDMcwi）背景下的CD 14基因中创建了靶向突变，并通过质谱法验证了CD 14肽的不存在。使用无线电遥测技术监测高盐激发的野生型和CD 14 −/−动物的血压，并通过流式细胞术鉴定浸润的肾脏免疫细胞。CD 14的种系敲除加重了雌性动物的盐敏感性高血压和肾损伤，但对雄性动物无影响。CD 14 −/−女性表现出浸润性巨噬细胞增加，但浸润性淋巴细胞无差异。使用CD 14 +/+或CD 14 −/−骨髓移植来分离CD 14敲除对造血细胞的影响，并证实观察到的差异表型是由于造血细胞中CD 14的敲除。卵巢切除术用于消除雌性激素的影响，这完全消除了CD 14基因敲除的效果。这些研究提供了一种新的治疗靶点，并证明了在CD 14调节免疫细胞活化和肾损伤的高血压疾病背景下，性别之间的免疫活化存在新的二分法。
Genomic sequence and gene expression association studies in animals and humans have identified genes that may be integral in the pathogenesis of various diseases. CD14 (cluster of differentiation 14)—a cell surface protein involved in innate immune system activation—is one such gene associated with cardiovascular and hypertensive disease. We previously showed that this gene is upregulated in renal macrophages of Dahl salt-sensitive animals fed a high-salt diet; here we test the hypothesis that CD14 contributes to the elevated pressure and renal injury observed in salt-sensitive hypertension. Using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9), we created a targeted mutation in theCD14gene on the Dahl SS (SS/JrHSDMcwi) background and validated the absence of CD14 peptides via mass spectrometry. Radiotelemetry was used to monitor blood pressure in wild-type and CD14−/−animals challenged with high salt and identified infiltrating renal immune cells via flow cytometry. Germline knockout of CD14 exacerbated salt-sensitive hypertension and renal injury in female animals but not males. CD14−/−females demonstrated increased infiltrating macrophages but no difference in infiltrating lymphocytes. Transplant of CD14+/+or CD14−/−bone marrow was used to isolate the effects of CD14 knockout to hematopoietic cells and confirmed that the differential phenotype observed was due to knockout of CD14 in hematopoietic cells. Ovariectomy was used to remove the influence of female sex hormones, which completely abrogated the effect of CD14 knockout. These studies provide a novel treatment target and evidence of a new dichotomy in immune activation between sexes within the context of hypertensive disease where CD14 regulates immune cell activation and renal injury.