A novel mouse model of adenine-supplemented high-fat diet induced cardiovascular-kidney-metabolic syndrome

Abstract Cardiovascular-kidney-metabolic (CKM) syndrome, a recently proposed concept focusing on the interrelationship among cardiovascular system, chronic kidney disease, and metabolic risk factors, is associated with high morbidity and mortality. The mechanism of CKM syndrome has not yet been fully examined due to the lack of an animal model. Here, we investigated whether an adenine-supplemented high-fat diet (AHFD) can induce CKM syndrome in mice. We fed normal chow diet (NCD), adenine-supplemented diet (AD), high-fat diet (HFD), and 0.15% AHFD to 129×1/Sv mice for 16 weeks and 0.2%AHFD to 129×1/Sv for 6 weeks. Also, C57BL/6 N mice were fed with 0.15%AHFD for 16 weeks. Metabolic parameters, blood pressure, organ weights, histology, and RNA sequencing were analyzed. The 0.15%AHFD group exhibited hypercholesterolemia, elevated blood pressure, kidney atrophy with fibrosis, and cardiac hypertrophy with interstitial fibrosis. Both kidney and cardiac RNA sequencing in the 0.15%AHFD group revealed upregulation of inflammatory and immune-related gene sets, whereas genes involved in cardiac contraction were downregulated. In contrast, 0.2%AHFD induced body weight loss, severe kidney dysfunction, and cardiac atrophy without functional impairment in 129×1/Sv mice. Of note, the C57BL/6 N mice exhibited metabolic abnormality and cardiac hypertrophy with diastolic dysfunction after 0.15%AHFD feeding despite mild renal dysfunction. We report a novel mouse model of CKM syndrome with dietary intervention, which exhibits fibrosis and myocardial hypertrophy in the heart. This model could be a valuable tool for analyzing the mechanism of CKM syndrome and assessing therapeutic options.