Abstract
BackgroundMitochondria hold crucial importance in organs with high energy demand especially the heart. We investigated whether chronic kidney disease (CKD), which eventually culminates in cardiorenal syndrome, could affect cardiac mitochondria and assessed the potential involvement of angiotensin II (AngII) in the process.MethodsMale Lewis rats underwent 5/6 nephrectomy allowing CKD development for eight months or for eleven weeks. Short-term CKD rats were administered with AngII receptor blocker (ARB). Cardiac function was assessed by echocardiography and cardiac sections were evaluated for interstitial fibrosis and cardiomyocytes’ hypertrophy. Electron microscopy was used to explore the spatial organization of the cardiomyocytes. Expression levels of mitochondrial content and activity markers were tested in order to delineate the underlying mechanisms for mitochondrial pathology in the CKD setting with or without ARB administration.ResultsCKD per-se resulted in induced cardiac interstitial fibrosis and cardiomyocytes’ hypertrophy combined with a marked disruption of the mitochondrial structure. Moreover, CKD led to enhanced cytochrome C leakage to the cytosol and to enhanced PARP-1 cleavage which are associated with cellular apoptosis. ARB treatment did not improve kidney function but markedly reduced left ventricular mass, cardiomyocytes’ hypertrophy and interstitial fibrosis. Interestingly, ARB administration improved the spatial organization of cardiac mitochondria and reduced their increased volume compared to untreated CKD animals. Nevertheless, ARB did not improve mitochondrial content, mitochondrial biogenesis or the respiratory enzyme activity. ARB mildly upregulated protein levels of mitochondrial fusion-related proteins.ConclusionsCKD results in cardiac pathological changes combined with mitochondrial damage and elevated apoptotic markers. We anticipate that the increased mitochondrial volume mainly represents mitochondrial swelling that occurs during the pathological process of cardiac hypertrophy. Chronic administration of ARB may improve the pathological appearance of the heart. Further recognition of the molecular pathways leading to mitochondrial insult and appropriate intervention is of crucial importance.
Highlights
Kidney dysfunction and cardiac dysfunction are frequently associated, leading to cardiorenal syndrome (CRS)—a grave condition with growing morbidity and mortality rate
We investigated whether chronic kidney disease (CKD), which eventually culminates in cardiorenal syndrome, could affect cardiac mitochondria and assessed the potential involvement of angiotensin II (AngII) in the process
AngII receptor blocker (ARB) administration improved the spatial organization of cardiac mitochondria and reduced their increased volume compared to untreated CKD animals
Summary
Kidney dysfunction and cardiac dysfunction are frequently associated, leading to cardiorenal syndrome (CRS)—a grave condition with growing morbidity and mortality rate. It has become clear that cardiovascular involvement occurs in each stage of CKD and that major cardiac events represent almost 50% of the causes of death in CKD patients.[7] the tight interplay between kidney and heart exposes individuals with a relatively minor reduction in estimated glomerular filtration rate to an increased risk of cardiovascular events and death.[5]. We investigated whether chronic kidney disease (CKD), which eventually culminates in cardiorenal syndrome, could affect cardiac mitochondria and assessed the potential involvement of angiotensin II (AngII) in the process
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