Chronic Kidney Disease Initiates AngII-depended Cardiac Mitochondrial Dysfunction

Background- Mitochondria hold crucial importance in organs which demand high energy such as the heart. Therefore we investigated whether chronic kidney disease (CKD), which eventually leads to cardiorenal syndrome (CRS), affects cardiac mitochondria and if so, to assess the potential involvement of angiotensin II (AngII), a known hallmark of CKD.

Methods- Male Lewis rats underwent 5/6 nephrectomy allowing CKD development, and treated with either AngII receptor blocker (ARB) to block the AngII signal or with vehicle only. At end of experiment blood pressure (BP), heart function (echocardiography) and kidney function were documented and cardiac samples were obtained. Electron microscopy was performed to explore cardiac mitochondrial structure. Cytochrome B expression was tested to determine total mitochondrial DNA content. Active mitochondrial content was assessed by the mitochondrial marker enzyme, citrate synthase enzymatic activity. Respiratory chain function in isolated mitochondria was determined by enzymatic assays of complexes I-IV. Mitochondrial quality control processes, fission and fusion, were assessed by genes expression analyses.

Results- ARB treatment did not improve kidney function but partly attenuated BP, markedly attenuated LV mass, and significantly reduced cardiac hypertrophy and fibrosis. In addition, ARB reduced cardiac AngII receptor levels. CKD per-se resulted in cardiac mitochondrial changes of structure (swollen) and function (reduced active mitochondria content). Interestingly, ARB partially attenuated cardiac mitochondrial volume increase (by 13%) but did not improve mitochondrial content and respiratory enzyme activity. Surprisingly, ARB treatment attenuated overexpression of fusion gene (OPA1 by 22%) and fission genes (DRP1 by 30% and Fis1 by 39%).

Conclusions- AngII may be involved, at least in part, in mitochondrial attenuation in the CKD setting. Specifically, our data demonstrate that chronic administration of ARB improves cardiac mitochondrial morphology partly by affecting the mitochondrial quality control mechanisms. Further recognition of the molecular pathways leading to mitochondrial insult and appropriate intervention is of crucial importance.