<b>Mapping cardiac remodeling in chronic kidney disease</b>

Patients with advanced chronic kidney disease (CKD) mostly die from sudden cardiac death and recurrent heart failure. The mechanisms of cardiac remodeling in these patients are largely unclear. To dissect molecular and cellular mechanisms of cardiac remodeling in CKD in an unbiased fashion, we performed left ventricular single-nuclear RNA-sequencing in two mouse models of CKD. Our data showed a hypertrophic response trajectory of cardiomyocytes with stress signaling and metabolic changes driven by soluble uremia related factors. We mapped fibroblast to myofibroblast differentiation in this process and identified significant changes in the cardiac vasculature, suggesting inflammation and dysfunction. An integrated analysis of cardiac cellular responses to uremic toxins pointed towards endothelin-1 and methylglyoxal (MGO) being involved in capillary dysfunction and TNF-a driving cardiomyocyte hypertrophy in CKD which was validated <i>in vitro</i> and <i>in vivo</i>. TNF-a inhibition in vivo ameliorated the cardiac phenotype in CKD. Thus, interventional approaches directed against uremic toxins, such as TNFa, hold promise to ameliorate cardiac remodeling in CKD.晚期慢性肾脏病（CKD）患者大多死于心搏骤停与复发性心力衰竭，此类患者心脏重构的分子机制在很大程度上仍未阐明。为无偏倚地解析慢性肾脏病患者心脏重构的分子与细胞机制，我们在两种慢性肾脏病小鼠模型中开展了左心室单细胞核RNA测序（single-nuclear RNA-sequencing）。我们的研究数据显示，心肌细胞存在以可溶性尿毒症相关因子驱动的应激信号通路激活与代谢改变的肥厚反应轨迹。我们在此过程中绘制了成纤维细胞向肌成纤维细胞的分化图谱，并发现心脏血管系统出现显著变化，提示存在炎症反应与血管功能异常。针对尿毒症毒素的心脏细胞应答整合分析表明，内皮素-1与乙二醛（MGO）参与了毛细血管功能障碍，而肿瘤坏死因子-α（TNF-α）则驱动慢性肾脏病中的心肌细胞肥厚，该结论已在体外（in vitro）与体内（in vivo）实验中得到验证。体内抑制肿瘤坏死因子-α可改善慢性肾脏病小鼠的心脏表型。因此，针对肿瘤坏死因子-α这类尿毒症毒素的干预手段，有望改善慢性肾脏病患者的心脏重构。

搜集汇总

背景与挑战

背景概述

该数据集通过小鼠模型的单核RNA测序数据，研究慢性肾病（CKD）中心脏重塑的机制，重点关注心肌细胞肥大、成纤维细胞分化和血管功能障碍。数据集揭示了尿毒症毒素（如TNF-α）在驱动心脏病变中的作用，并验证了干预措施的有效性，为理解CKD相关心脏并发症提供了分子层面的见解。