Biomarkers of cardio-renal syndrome in uremic myocardiopathy animal model

ABSTRACT Introduction: Cardio-renal syndrome subtype 4 (CRS4) is a condition of primary chronic kidney disease that leads to reduction of cardiac function, ventricular hypertrophy, and risk of cardiovascular events. Objective: Our aim was to understand the mechanisms involved on the onset of CRS4. Methods: We used the nephrectomy 5/6 (CKD) animal model and compared to control (SHAM). Serum biomarkers were analyzed at baseline, 4, and 8 weeks. After euthanasia, histology and immunohistochemistry were performed in the myocardium. Results: Troponin I (TnI) was increased at 4 weeks (W) and 8W, but nt-proBNP showed no difference. The greater diameter of cardiomyocytes indicated left ventricular hypertrophy and the highest levels of TNF-α were found at 4W declining in 8W while fibrosis was more intense in 8W. Angiotensin expression showed an increase at 8W. Conclusions: TnI seems to reflect cardiac injury as a consequence of the CKD however nt-proBNP did not change because it reflects stretching. TNF-α characterized an inflammatory peak and fibrosis increased over time in a process connecting heart and kidneys. The angiotensin showed increased activity of the renin-angiotensin axis and corroborates the hypothesis that the inflammatory process and its involvement with CRS4. Therefore, this animal study reinforces the need for renin-angiotensin blockade strategies and the control of CKD to avoid the development of CRS4.

摘要
引言：心肾综合征4型（Cardio-renal syndrome subtype 4, CRS4）是一类由原发性慢性肾病引发的病症，可导致心功能下降、心室肥厚及心血管事件风险升高。
研究目的：阐明心肾综合征4型（CRS4）的发病机制。
研究方法：采用5/6肾切除慢性肾病（chronic kidney disease, CKD）动物模型，并以假手术（SHAM）组作为对照。分别于基线期、第4周及第8周检测血清生物标志物。实验动物处死后，对心肌组织开展组织学与免疫组化分析。
研究结果：肌钙蛋白I（Troponin I, TnI）在第4周及第8周均表达升高，但N末端B型利钠肽原（N-terminal pro-B-type natriuretic peptide, nt-proBNP）无显著变化。心肌细胞直径增大提示左心室肥厚，肿瘤坏死因子-α（Tumor Necrosis Factor-α, TNF-α）水平在第4周达到峰值，于第8周有所回落，而心肌纤维化程度在第8周更为显著。血管紧张素的表达在第8周出现升高。
研究结论：肌钙蛋白I（TnI）可反映慢性肾病继发的心肌损伤，但N末端B型利钠肽原（nt-proBNP）未出现明显改变，因其反映的是心肌牵拉状态。肿瘤坏死因子-α（TNF-α）体现了炎症反应的峰值特征，心肌纤维化随时间推移逐渐加重，这一过程连接了心肾二者的病理关联。血管紧张素表达升高提示肾素-血管紧张素轴活性增强，印证了炎症过程参与心肾综合征4型（CRS4）发病的假说。本动物实验进一步证实，需采取肾素-血管紧张素阻断策略并控制慢性肾病病情，以避免心肾综合征4型（CRS4）的发生发展。