Pathological presentation of cardiac mitochondria in a rat model for chronic kidney disease

Figures

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  Fig 1. CKD-mediated systemic effects on the neurohumoral and immune systems. Plasma levels of Angiotensin II (A); and Pro- and anti-inflammatory cytokine profile (B) in plasma samples of CKD rats (n = 3) compared to sham (n = 4). Data are represented as mean ± SEM. ** p<0.01,* p<0.05.

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  Fig 2. CKD setting enhances cardiac fibrosis, cardiomyocytes’ hypertrophy and cardiac mitochondrial swelling. (A) Representative Masson’s trichrome captures of interstitial fibrosis and quantification as percent of fibrosis out of total area (%). Magnification is x20. (B) FITC-WGA staining to assess myocytes’ hypertrophy; Magnification is x40. (C) Representative TEM micrographs and quantification of the mitochondrial volume out of total area of the field (%). Yellow circles mark the mitochondrial area and arrow heads mark swollen-deranged mitochondria. Magnification is x12K. Quantification analysis was derived from 4 fields per slides; 5–6 animals/group. Data are represented as mean ± SEM. pA is based on Mann-Whitney test, otherwise p-value is based on two-tailed t-test.

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  Fig 3. ARB treatment reduces cardiac interstitial fibrosis, cardiomyocytes’ hypertrophy and total volume of the cardiac mitochondria. (A) Representative Masson’s trichrome captures of interstitial fibrosis (%). Magnification X20. (B) FITC-WGA staining to assess myocyte hypertrophy (μm). Magnification X40. (C) Representative TEM micrographs as well as quantification of the mitochondrial volume out of total area of the field (%). Yellow circles mark the mitochondrial area and arrow heads mark swollen-deranged mitochondria. Magnification is x12K. Quantification was derived from 4 fields per slides; 4–7 animals/group. ARB–CKD animals treated with ARB. Data are represented as mean ± SEM. * P<0.05.

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  Fig 4. CKD-induced mitochondrial damage. (A) Relative expression of CytB as a marker for total mitochondrial content, relative to 18S. (B) Citrate synthase activity as an indicator for intact mitochondrial content. (C) Protein expression of PGC1α as a marker for mitochondrial biogenesis, normalized to GAPDH. (D) ATP synthase (complex V) activity. All data are given for the 3 experimental groups: sham, CKD and ARB (4–6 animals/group). ARB–CKD animals treated with ARB. Data are represented as mean ± SEM.

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  Fig 5. Mitochondrial biogenesis and quality control. Protein expression of the fission protein MFN1 as well as the fusion proteins FIS1 and DRP1. N = 4–6 animals/group. ARB–CKD animals treated with ARB. Data are represented as mean ± SEM.

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  Fig 6. Potential mechanisms for CKD-induced mitochondrial damage. (A) Relative CytC expression (CytC leakage) in cytosolic fractions of cardiac cells. (B) Protein expression of PARP-1 as a marker for cellular apoptosis, normalized to GAPDH. N = 4–6 animals/group. ARB–CKD animals treated with ARB. Data are represented as mean ± SEM.

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  Fig 7. A potential kidney-heart interplay which may mediate changes in mitochondrial structure and function in CKD. (A) CKD setting results in cardiac gross pathology (manifested by increased fibrosis, LV mass and cellular hypertrophy) as well as mitochondrial abnormality (manifested by mitochondrial swelling, decreased mitochondrial content and active mitochondrial content) through mild elevation in blood pressure and activation of neurohumoral and immune systems. These changes may lead to the progression of CKD to CRS type 4. (B) ARB treatment mainly attenuates changes in the gross pathology of the heart as well as mitochondrial abnormalities.