BS24 Establishing a clinically relevant progressive model of ckd-associated cardiomyopathy in mice for insights into early-stage pathogenesis

Background Chronic kidney disease (CKD) affects 10–15% of the population globally. Reduced kidney function leads to CKD-associated cardiomyopathy characterised by increased left ventricular mass, diastolic and systolic dysfunction, and profound cardiac fibrosis. Despite high morbidity and mortality, CKD-associated cardiomyopathy remains poorly understood mechanistically. Current CKD animal models, like the 5/6 nephrectomy, primarily focus on late-stage CKD, hindering insights into early CKD-associated cardiomyopathy and progressive mechanistic actions. This limitation impedes the establishment of proactive therapeutic approaches. To address this gap, we propose characterizing a progressive murine model using an adenine-rich diet, allowing us to study the structural and functional differences between early and late-stage CKD-associated cardiomyopathy. Methods 8–9-week-old C57BL/6 male mice were fed either normal chow (n=9) or a 0.15% adenine rich diet (n=9), for up to 7 weeks. Blood levels of creatinine and urea were measured at 5 and 7 weeks to assess kidney dysfunction. Fibrosis was measured using western blotting and histology (via Martius Scarlet Blue staining). Heart, and kidney weight were recorded at the 5-week and 7-week endpoint, while body weight was measured weekly. Results Significant increases in both urea (p< 0.0001) and creatinine (p< 0.0001) were observed at 5 and 7 weeks on adenine diet compared to the control (figure 1). No significant increases in heart weights were observed. Additionally, kidney weight decreased significantly between the control (155.8±16.1 mg) and 7-week adenine mice (104.2±13.8 mg) (p<0.0001). Evidence of cardiac fibrosis was detected in adenine fed mice, as demonstrated by increased collagen 1 protein expression in whole heart homogenates (p< 0.05) and increased fibrosis staining using histology in all 4 chambers of the heart (p< 0.0001) (See figure 1). The largest increase in fibrosis was observed in the right atria, rising from an average of 2.16% in control mice to 4.87% in adenine fed mice (p<0.001). No significant changes in the heart weight, or heart to body weight ratio were detected in adenine fed mice compared to control. Conclusion Adenine diet induced kidney disease model demonstrated progressive reduction of kidney function over 7 weeks, accompanied by cardiac fibrosis but without overt hypertrophy. Further studies will utilise this model to gain insights into the mechanisms driving CKD-associated cardiomyopathy pathogenesis. Conflict of Interest None