背景:慢性肾脏病(CKD)是肺动脉高压(PH)的重要危险因素,对患者预后有不利影响的并发症。然而,这种关联的潜在机制仍然知之甚少.该领域进展的主要障碍是缺乏可靠的复制CKD-PH的动物模型。
方法:本研究旨在建立稳定的CKD-PH大鼠模型。我们采用了一种联合方法,通过5/6肾切除术诱导CKD,同时将大鼠暴露于高盐饮食。动态评估模型的血流动力学,同时对多个器官的病理变化进行全面评估。收集CKD-PH大鼠的肺组织和血清样本,分析血管紧张素转换酶2(ACE2)的表达,评估肾素-血管紧张素-醛固酮系统(RAAS)内关键血管成分的活性,并表征血清代谢谱的变化。
结果:手术后14周,CKD-PH大鼠表现出指示肺动脉高压的血流动力学参数的显著变化。此外,观察到右心室肥厚。值得注意的是,未发现肺血管重塑的证据.进一步分析显示CKD-PH大鼠肺血管内皮内RAAS失调和ACE2表达下调。此外,这些动物的血清代谢谱与假手术组明显不同。
结论:我们的发现表明,CKD-PH大鼠肺动脉高压的发展可能是一种综合效应的结果:RAAS失调,肺血管内皮细胞ACE2表达降低,和代谢紊乱。
BACKGROUND: Chronic kidney disease (CKD) is a significant risk factor for pulmonary hypertension (PH), a complication that adversely affects patient prognosis. However, the mechanisms underlying this association remain poorly understood. A major obstacle to progress in this field is the lack of a reliable animal model replicating CKD-PH.
METHODS: This study aimed to establish a stable rat model of CKD-PH. We employed a combined approach, inducing CKD through a 5/6 nephrectomy and concurrently exposing the rats to a high-salt diet. The model\'s hemodynamics were evaluated dynamically, alongside a comprehensive assessment of pathological changes in multiple organs. Lung tissues and serum samples were collected from the CKD-PH rats to analyze the expression of angiotensin-converting enzyme 2 (ACE2), evaluate the activity of key vascular components within the renin-angiotensin-aldosterone system (RAAS), and characterize alterations in the serum metabolic profile.
RESULTS: At 14 weeks post-surgery, the CKD-PH rats displayed significant changes in hemodynamic parameters indicative of pulmonary arterial hypertension. Additionally, right ventricular hypertrophy was observed. Notably, no evidence of pulmonary vascular remodeling was found. Further analysis revealed RAAS dysregulation and downregulated ACE2 expression within the pulmonary vascular endothelium of CKD-PH rats. Moreover, the serum metabolic profile of these animals differed markedly from the sham surgery group.
CONCLUSIONS: Our findings suggest that the development of pulmonary arterial hypertension in CKD-PH rats is likely a consequence of a combined effect: RAAS dysregulation, decreased ACE2 expression in pulmonary vascular endothelial cells, and metabolic disturbances.