A New Model of Chronic Kidney Disease, Metabolic Derangements, and Heart Failure with Preserved Ejection Fraction in Aging Swine.

IF 4.3 3区 医学 Q1 UROLOGY & NEPHROLOGY
Alejandro R Chade, Darla L Tharp, Rhys Sitz, Elizabeth A McCarthy, Kumar Shivam, Sara Kazeminia, Alfonso Eirin
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Abstract

Introduction: Chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF) are more prevalent in the elderly. There is a lack of large animal models that allow the study of the impact of age on CKD and HFpEF in a translational fashion. This manuscript reports the first large preclinical model of CKD-HFpEF and metabolic derangements in naturally aged swine.

Methods: CKD-HFpEF was induced in naturally aged (6-9 years old) and young (3 months old) pigs, followed for 14 weeks, and compared to normal young and old controls (n = 5/group). Renal and cardiac hemodynamics were quantified in vivo by multidetector-CT, echocardiography, and pressure-volume relationship studies. Renal and cardiac microvascular (MV) architecture (3D-micro-CT) and morphometric analysis (staining) were investigated ex vivo.

Results: Both young and old pigs developed CKD-HFpEF, but the renal, cardiac, and metabolic phenotype was accentuated in aging animals. Aging and CKD-HFpEF influenced fasting insulin levels and insulin resistance, glomerular filtration rate, cortical MV density, glomerulosclerosis, perivascular fibrosis, and tubular injury. Tubule-interstitial fibrosis and peritubular capillary density were influenced by aging, CKD-HFpEF, and their interaction (2-way ANOVA). Similarly, cardiac MV density, perivascular fibrosis, and myocardial remodeling were influenced by aging and CKD-HFpEF, and E/A by their interaction. Notably, renal and cardiac MV density correlated with renal and cardiac functional and structural changes.

Conclusion: Our study establishes the first large animal model of aging CKD-HFpEF, allowing the investigation of age as a biological variable in cardiorenal and metabolic diseases. This new platform could foster new age-related research toward developing therapeutic interventions in CKD-HFpEF.

衰老猪慢性肾脏疾病、代谢紊乱和心力衰竭的新模型。
慢性肾脏疾病(CKD)和心力衰竭伴保留射血分数(HFpEF)在老年人中更为普遍。目前还缺乏大型动物模型来研究年龄对CKD和HFpEF的影响。这篇论文报道了第一个大型CKD-HFpEF和自然衰老猪代谢紊乱的临床前模型。方法:采用自然龄(6-9岁)和幼龄(3月龄)猪进行CKD-HFpEF诱导,随访14周,并与正常幼龄和老龄对照组(n=5/组)进行比较。通过多探头ct、超声心动图和压力-容积关系研究,定量体内肾脏和心脏血流动力学。体外研究肾脏和心脏微血管(MV)结构(3D-micro-CT)和形态计量学分析(染色)。结果:幼猪和老龄猪均发生CKD-HFpEF,但老龄动物的肾脏、心脏和代谢表型加重。衰老和CKD-HFpEF影响空腹胰岛素水平和胰岛素抵抗、GFR、皮质MV密度、肾小球硬化、血管周围纤维化和小管损伤。小管间质纤维化和小管周围毛细血管密度受年龄、CKD-HFpEF及其相互作用的影响(双因素方差分析)。同样,心脏MV密度、血管周围纤维化和心肌重构也受到衰老和CKD-HFpEF的影响,E/A也受到它们相互作用的影响。值得注意的是,肾脏和心脏的MV密度与肾脏和心脏的功能和结构变化相关。结论:我们的研究建立了第一个衰老CKD-HFpEF的大型动物模型,从而可以研究年龄作为心肾和代谢性疾病的生物学变量。这个新的平台可以促进新的与年龄相关的研究,以开发CKD-HFpEF的治疗干预措施。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
American Journal of Nephrology
American Journal of Nephrology 医学-泌尿学与肾脏学
CiteScore
7.50
自引率
2.40%
发文量
74
审稿时长
4-8 weeks
期刊介绍: The ''American Journal of Nephrology'' is a peer-reviewed journal that focuses on timely topics in both basic science and clinical research. Papers are divided into several sections, including:
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