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1.
Cells ; 10(12)2021 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-34943790

RESUMEN

Chronic kidney disease (CKD) results in reduced kidney function, uremia, and accumulation of uremic metabolites. Mitochondrial alterations have been suggested to play a role in the disease pathology within various tissues. The purpose of this study was to perform a comprehensive bioenergetic and proteomic phenotyping of mitochondria from skeletal muscle (SkM), cardiac muscle (CM), and renal tissue from mice with CKD. The 5-month-old C57BL/6J male mice were fed a casein control or adenine-supplemented diet for 6 months. CKD was confirmed by blood urea nitrogen. A mitochondrial diagnostic workflow was employed to examine respiratory function, membrane and redox potential, reactive oxygen species production, and maximal activities of matrix dehydrogenases and electron transport system (ETS) protein complexes. Additionally, tandem-mass-tag-assisted proteomic analyses were performed to uncover possible differences in mitochondrial protein abundance. CKD negatively impacted mitochondrial energy transduction (all p < 0.05) in SkM, CM, and renal mitochondria, when assessed at physiologically relevant cellular energy demands (ΔGATP) and revealed the tissue-specific impact of CKD on mitochondrial health. Proteomic analyses indicated significant abundance changes in CM and renal mitochondria (115 and 164 proteins, p < 0.05), but no differences in SkM. Taken together, these findings reveal the tissue-specific impact of chronic renal insufficiency on mitochondrial health.


Asunto(s)
Metabolismo Energético , Mitocondrias/metabolismo , Especificidad de Órganos , Proteómica , Insuficiencia Renal Crónica/metabolismo , Adenina/administración & dosificación , Animales , Transporte de Electrón , Conducta Alimentaria , Peróxido de Hidrógeno/metabolismo , Riñón/patología , Masculino , Potencial de la Membrana Mitocondrial , Ratones Endogámicos C57BL , Mitocondrias/enzimología , Proteínas Mitocondriales/metabolismo , NAD/metabolismo , Oxidación-Reducción , Fenotipo , Proteoma/metabolismo
2.
Am J Physiol Renal Physiol ; 321(1): F106-F119, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34121452

RESUMEN

Preclinical animal models of chronic kidney disease (CKD) are critical to investigate the underlying mechanisms of disease and to evaluate the efficacy of novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (Nx) CKD models in mice. Male and female 10-wk-old C57BL/6J mice (n = 5-9 mice/sex/group) were randomly allocated to CKD groups (0.2-0.15% adenine-supplemented diet or 5/6 Nx surgery) or the corresponding control groups (casein diet or sham surgery). Following the induction of CKD, the glomerular filtration rate was reduced to a similar level in both adenine and 5/6 Nx mice (adenine diet-fed male mice: 81.1 ± 41.9 µL/min vs. 5/6 Nx male mice: 160 ± 80.9 µL/min, P = 0.5875; adenine diet-fed female mice: 112.9 ± 32.4 µL/min vs. 5/6 Nx female mice: 107.0 ± 45.7 µL/min, P = 0.9995). Serum metabolomics analysis indicated that established uremic toxins were robustly elevated in both CKD models, although some differences were observed between CKD models (i.e., p-cresol sulfate). Dysregulated phosphate homeostasis was observed in the adenine model only, whereas Ca2+ homeostasis was disturbed in male mice with both CKD models. Compared with control mice, muscle mass and myofiber cross-sectional areas of the extensor digitorum longus and soleus muscles were ∼18-24% smaller in male CKD mice regardless of the model but were not different in female CKD mice (P > 0.05). Skeletal muscle mitochondrial respiratory function was significantly decreased (19-24%) in CKD mice in both models and sexes. These findings demonstrate that adenine diet and 5/6 Nx models of CKD have similar levels of renal dysfunction and skeletal myopathy. However, the adenine diet model demonstrated superior performance with regard to mortality (∼20-50% mortality for 5/6 Nx vs. 0% mortality for the adenine diet, P < 0.05 for both sexes) compared with the 5/6 Nx surgical model.NEW & NOTEWORTHY Numerous preclinical models of chronic kidney disease have been used to evaluate skeletal muscle pathology; however, direct comparisons of popular models are not available. In this study, we compared adenine-induced nephropathy and 5/6 nephrectomy models. Both models produced equivalent levels of muscle atrophy and mitochondrial impairment, but the adenine model exhibited lower mortality rates, higher consistency in uremic toxin levels, and dysregulated phosphate homeostasis compared with the 5/6 nephrectomy model.


Asunto(s)
Adenina/farmacología , Tasa de Filtración Glomerular/genética , Músculo Esquelético/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Modelos Animales de Enfermedad , Riñón/metabolismo , Riñón/patología , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/patología , Enfermedades Musculares/patología , Enfermedades Musculares/fisiopatología , Nefrectomía/métodos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Uremia/fisiopatología
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