Chronic kidney disease exacerbates ischemic limb myopathy in mice via altered mitochondria! energetics
Chronic kidney disease exacerbates ischemic limb myopathy in mice via altered mitochondria! energetics
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DOI：
10.1038/s41598-019-52107-7
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发表时间：
2019-10-29
影响因子：
4.6
通讯作者：
Ryan, Terence E.
中科院分区：
文献类型：
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作者：
Berru, Fabian N.;Gray, Sarah E.;Ryan, Terence E.
慢性肾脏病（CKD）显著增加了外周动脉疾病（PAD）的病理学严重程度，但其生物学机制尚不清楚。本文的目的是确定CKD对小鼠PAD病理学的影响。通过递送腺嘌呤六周，对C57 BL 6/J小鼠进行饮食诱导的CKD模型。通过测量肾小球滤过率、血尿素氮和肾组织病理学证实CKD。慢性肾脏病小鼠表现出较低的肌肉力量产生和胫骨前肌缺血性病变更大，（78.1 +/- 14.5%对比对照小鼠中的2.5 +/- 0.5%，P < 0.0001，N = 5-10/组）和肌纤维尺寸减小（1661 +/- 134 μ m（2）对对照小鼠的2221 +/- 100 μ m（2），P < 0.01，N= 5-10/组）。尽管毛细血管密度（516 +/- 59 vs. 466 +/- 45毛细血管/20 x视野）和肢体灌注正常，但仍发生骨骼肌病。CKD小鼠显示缺血肌肉中肌肉线粒体呼吸能力降低约50-65%，而对照小鼠具有正常的线粒体功能。慢性肾脏病小鼠缺血肌肉中过氧化氢的释放量略高，这与氧化剂缓冲能力下降相一致。将培养的肌管暴露于CKD血清导致肌萎缩和氧化应激升高，这通过线粒体I靶向治疗来减弱。总之，这些发现表明，由CKD引起的线粒体损伤有助于缺血性病理学的恶化。
Chronic kidney disease (CKD) substantially increases the severity of peripheral arterial disease (PAD) symptomology, however, the biological mechanisms remain unclear. The objective herein was to determine the impact of CKD on PAD pathology in mice. C57BL6/J mice were subjected to a dietinduced model of CKD by delivery of adenine for six weeks. CKD was confirmed by measurements of glomerular filtration rate, blood urea nitrogen, and kidney histopathology. Mice with CKD displayed lower muscle force production and greater ischemic lesions in the tibia lis anterior muscle (78.1 +/- 14.5% vs. 2.5 +/- 0.5% in control mice, P < 0.0001, N = 5-10/group) and decreased myofiber size (1661 +/- 134 mu m(2) vs. 2221 +/- 100 mu m(2) in control mice, P < 0.01, N= 5-10/group). This skeletal myopathy occurred despite normal capillary density (516 +/- 59 vs. 466 +/- 45 capillaries/20x field of view) and limb perfusion. CKD mice displayed a-50-65% reduction in muscle mitochondrial respiratory capacity in ischemic muscle, whereas control mice had normal mitochondrial function. Hydrogen peroxide emission was modestly higher in the ischemic muscle of CKD mice, which coincided with decreased oxidant buffering. Exposure of cultured myotubes to CKD serum resulted in myotu be atrophy and elevated oxidative stress, which were attenuated by mitochondria I-targeted therapies. Taken together, these findings suggest that mitochondrial impairments caused by CKD contribute to the exacerbation of ischemic pathology.