Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany.
Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany.
Redox Biol. 2022 Oct;56:102459. doi: 10.1016/j.redox.2022.102459. Epub 2022 Aug 30.
Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular events and exhibit myocardial changes including left ventricular (LV) hypertrophy and fibrosis, overall referred to as 'uremic cardiomyopathy'. Although different CKD animal models have been studied for cardiac effects, lack of consistent reporting on cardiac function and pathology complicates clear comparison of these models. Therefore, this study aimed at a systematic and comprehensive comparison of cardiac function and cardiac pathophysiological characteristics in eight different CKD models and mouse strains, with a main focus on adenine-induced CKD.
CKD of different severity and duration was induced by subtotal nephrectomy or adenine-rich diet in various strains (C57BL/6J, C57BL/6 N, hyperlipidemic C57BL/6J ApoE, 129/Sv), followed by the analysis of kidney function and morphology, blood pressure, cardiac function, cardiac hypertrophy, fibrosis, myocardial calcification and inflammation using functional, histological and molecular techniques, including cardiac gene expression profiling supplemented by oxidative stress analysis. Intriguingly, despite uremia of variable degree, neither cardiac dysfunction, hypertrophy nor interstitial fibrosis were observed. However, already moderate CKD altered cardiac oxidative stress responses and enhanced oxidative stress markers in each mouse strain, with cardiac RNA sequencing revealing activation of oxidative stress signaling as well as anti-inflammatory feedback responses.
This study considerably expands the knowledge on strain- and protocol-specific differences in the field of cardiorenal research and reveals that several weeks of at least moderate experimental CKD increase oxidative stress responses in the heart in a broad spectrum of mouse models. However, this was insufficient to induce relevant systolic or diastolic dysfunction, suggesting that additional "hits" are required to induce uremic cardiomyopathy.
Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular adverse events and exhibit myocardial changes, overall referred to as 'uremic cardiomyopathy'. We revealed that CKD increases cardiac oxidative stress responses in the heart. Nonetheless, several weeks of at least moderate experimental CKD do not necessarily trigger cardiac dysfunction and remodeling, suggesting that additional "hits" are required to induce uremic cardiomyopathy in the clinical setting. Whether the altered cardiac oxidative stress balance in CKD may increase the risk and extent of cardiovascular damage upon additional cardiovascular risk factors and/or events will be addressed in future studies.
慢性肾脏病（CKD）患者发生心血管事件的风险增加，并表现出心肌变化，包括左心室（LV）肥大和纤维化，统称为“尿毒症性心肌病”。尽管已经研究了不同的 CKD 动物模型对心脏的影响，但由于缺乏对心脏功能和病理学的一致报告，使得这些模型的明确比较变得复杂。因此，本研究旨在对 8 种不同 CKD 模型和小鼠品系的心脏功能和心脏病理生理特征进行系统和全面的比较，主要关注腺嘌呤诱导的 CKD。
通过半肾切除术或富含腺嘌呤的饮食在不同品系（C57BL/6J、C57BL/6N、高脂血症 C57BL/6J ApoE、129/Sv）中诱导不同严重程度和持续时间的 CKD，然后使用功能、组织学和分子技术分析肾功能和形态、血压、心脏功能、心脏肥大、纤维化、心肌钙化和炎症，包括心脏基因表达谱分析和氧化应激分析。有趣的是，尽管存在不同程度的尿毒症，但未观察到心脏功能障碍、肥大或间质纤维化。然而，即使是中度 CKD 也改变了心脏的氧化应激反应，并增强了每种小鼠品系的氧化应激标志物，心脏 RNA 测序显示氧化应激信号的激活以及抗炎反馈反应。
本研究大大扩展了心脏肾研究领域中品系和方案特异性差异的知识，并揭示了至少数周的中度实验性 CKD 在广泛的小鼠模型中增加了心脏的氧化应激反应。然而，这不足以引起相关的收缩或舒张功能障碍，这表明需要额外的“打击”来诱导尿毒症性心肌病。
慢性肾脏病（CKD）患者发生心血管不良事件的风险增加，并表现出心肌变化，统称为“尿毒症性心肌病”。我们发现 CKD 增加了心脏的氧化应激反应。尽管如此，至少数周的中度实验性 CKD 不一定会引发心脏功能障碍和重塑，这表明在临床环境中需要额外的“打击”来诱导尿毒症性心肌病。在未来的研究中，将探讨 CKD 中改变的心脏氧化应激平衡是否会增加额外的心血管危险因素和/或事件对心血管损伤的风险和程度。
