Development of a Mouse Model of Uremic Cardiomyopathy: Investigating the Impact of Chronic Kidney Disease on Cardiac Function and Signaling Pathway

Patients with chronic kidney disease are at an increased risk of developing heart failure, but the underlying mechanisms remain incompletely understood, at least in part because of the paucity of mouse models of uremic cardiomyopathy. In this study, we used two different experimental setups of 2,8-dihydroxyadenine-induced nephropathy in different mouse strains to develop a non-invasive mouse model of uremic cardiomyopathy. Among the different models, only 129/Sv mice fed an adenine-supplemented diet for 16 weeks showed typical features of uremic cardiomyopathy. Kidney damage was confirmed by histopathologic findings of diffuse fibrosis with collagen deposition, crystal formation, and uremia. The cardiac phenotype showed significantly increased myocardial fibrosis associated with impaired cardiac contractility under dobutamine-induced stress conditions. This was associated with a significant activation of the mTOR pathway and downstream endoplasmic reticulum stress, increased apoptosis, and inflammation. Treatment of 129/Sv mice with an adenine-supplemented diet for 16 weeks represents a model of uremic cardiomyopathy with increased myocardial fibrosis and impaired cardiac function, as well as a shift from cardioprotective to detrimental signaling, increased endoplasmic reticulum stress, and inflammation.