In Chronic Kidney Disease Altered Cardiac Metabolism Precedes Cardiac Hypertrophy

Conduit arterial disease in CKD is an important cause of cardiac complications. Cardiac function in CKD has not been studied in the absence of arterial disease. In an Alport syndrome model bred not to have conduit arterial disease, mice at 225 days of life (dol) had CKD equivalent to human stage 4-5 CKD. PTH and FGF23 levels were one log order elevated, circulating sclerostin was elevated, and renal activin A was strongly induced. Aortic Ca levels were not increased and VSMC transdifferentiation was absent. The CKD mice were not hypertensive, and cardiac hypertrophy was absent. Freshly excised cardiac tissue respirometry (Oroboros) showed ADP-stimulated O2 flux was diminished from 52 to 22 pmol/mg (p=0.022). RNAseq of cardiac tissue from CKD mice revealed significantly decreased levels of cardiac mitochondrial oxidative phosphorylation genes. The data reported here show that cardiac mitochondrial respiration is impaired in CKD in the absence of conduit arterial disease. This is the first report of the direct effect of CKD on cardiac respiration. Overall design: To investigate heart function in a murine model of chronic kidney disese, we aged collagen IV knockout and wild type animals to 225 days of life and then excised left ventricle tissue for respirometry and RNA-seq analysis. There are 8 wild type and 7 mutant CKD biological replicates.