Moellmann Julia, Glandien Katja, Klinkhammer Barbara M, Wollenhaupt Julia, Noels Heidi, Jankowski Joachim, Lebherz Corinna, Boor Peter, Lehrke Michael, Marx Nikolaus
Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
FASEB J. 2025 May 31;39(10):e70639. doi: 10.1096/fj.202500281R.
Patients with chronic kidney disease are at an increased risk of developing heart failure, but the underlying mechanisms remain incompletely understood, at least in part because of the paucity of mouse models of uremic cardiomyopathy. In this study, we used two different experimental setups of 2,8-dihydroxyadenine-induced nephropathy in different mouse strains to develop a non-invasive mouse model of uremic cardiomyopathy. Among the different models, only 129/Sv mice fed an adenine-supplemented diet for 16 weeks showed typical features of uremic cardiomyopathy. Kidney damage was confirmed by histopathologic findings of diffuse fibrosis with collagen deposition, crystal formation, and uremia. The cardiac phenotype showed significantly increased myocardial fibrosis associated with impaired cardiac contractility under dobutamine-induced stress conditions. This was associated with a significant activation of the mTOR pathway and downstream endoplasmic reticulum stress, increased apoptosis, and inflammation. Treatment of 129/Sv mice with an adenine-supplemented diet for 16 weeks represents a model of uremic cardiomyopathy with increased myocardial fibrosis and impaired cardiac function, as well as a shift from cardioprotective to detrimental signaling, increased endoplasmic reticulum stress, and inflammation.
慢性肾脏病患者发生心力衰竭的风险增加，但其潜在机制仍未完全明确，至少部分原因是尿毒症心肌病小鼠模型的匮乏。在本研究中，我们在不同小鼠品系中使用两种不同的2,8 - 二羟基腺嘌呤诱导肾病的实验设置，以建立一种非侵入性的尿毒症心肌病小鼠模型。在不同模型中，只有喂食含腺嘌呤饮食16周的129/Sv小鼠表现出尿毒症心肌病的典型特征。通过弥漫性纤维化伴胶原沉积、晶体形成和尿毒症的组织病理学发现证实了肾脏损伤。心脏表型显示，在多巴酚丁胺诱导的应激条件下，心肌纤维化显著增加，同时心脏收缩功能受损。这与mTOR通路和下游内质网应激的显著激活、细胞凋亡增加以及炎症有关。用含腺嘌呤饮食喂养16周的129/Sv小鼠代表了一种尿毒症心肌病模型，其心肌纤维化增加、心脏功能受损，同时信号传导从心脏保护转向有害，内质网应激增加以及炎症反应增强。
