Persistent disruption of mitochondrial homeostasis after acute kidney injury
Persistent disruption of mitochondrial homeostasis after acute kidney injury
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DOI：
10.1152/ajprenal.00035.2011
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发表时间：
2012-04-01
影响因子：
4.2
通讯作者：
Schnellmann, Rick G.
中科院分区：
文献类型：
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作者：
Funk, Jason A.;Schnellmann, Rick G.
Funk JA，Schnellmann RG.急性肾损伤后线粒体稳态的持续破坏。美国肾脏生理学杂志302：F853-F864，2012年。首次发表于2011年12月7日; doi：10.1152/ajprenal.00035.2011。虽然线粒体功能障碍是急性肾损伤（阿基）后发生的病理过程，但阿基损伤和恢复阶段的线粒体稳态状态仍不清楚。我们研究了两种非致死性啮齿动物阿基模型中线粒体稳态的标志物。通过向大鼠注射甘油诱导肌红蛋白尿性阿基，并使小鼠经受缺血性阿基。两种模型中的动物在损伤后24小时血清肌酐升高，表明肾功能不全，在损伤后144小时部分恢复。近端小管功能/损伤的标志物，包括中性粒细胞明胶酶相关脂质运载蛋白和尿糖，在同一时期没有恢复。持续的半胱天冬酶3裂解和小管扩张和刷状缘损伤的证据证实了持续的病理状态。在两种损伤模型中，呼吸蛋白NDUFB 8、ATP合酶β、细胞色素c氧化酶亚基I（考克斯I）和考克斯IV均降低，并且在144 h时未恢复。免疫组织化学分析证实，考克斯IV蛋白在缺血再灌注（I/R）后肾皮质近端小管进行性丢失。线粒体分裂蛋白Drp 1的表达在两种模型中损伤后升高，而融合蛋白Mfn 2在甘油损伤后升高，但在I/阿基后降低。LC 3-I/II表达显示，在两种损伤模型中，自噬在随后的时间点增加。线粒体生物发生的标志物，如PGC-1 α和PRC，在两种模型中均升高。这些发现表明，即使在线粒体恢复信号和肾小球滤过改善的情况下，阿基后线粒体稳态持续破坏和持续肾小管损伤。
Funk JA, Schnellmann RG. Persistent disruption of mitochondrial homeostasis after acute kidney injury. Am J Physiol Renal Physiol 302: F853-F864, 2012. First published December 7, 2011; doi:10.1152/ajprenal.00035.2011.-While mitochondrial dysfunction is a pathological process that occurs after acute kidney injury (AKI), the state of mitochondrial homeostasis during the injury and recovery phases of AKI remains unclear. We examined markers of mitochondrial homeostasis in two nonlethal rodent AKI models. Myoglobinuric AKI was induced by glycerol injection into rats, and mice were subjected to ischemic AKI. Animals in both models had elevated serum creatinine, indicative of renal dysfunction, 24 h after injury which partially recovered over 144 h postinjury. Markers of proximal tubule function/injury, including neutrophil gelatinase-associated lipocalin and urine glucose, did not recover during this same period. The persistent pathological state was confirmed by sustained caspase 3 cleavage and evidence of tubule dilation and brush-border damage. Respiratory proteins NDUFB8, ATP synthase beta, cytochrome c oxidase subunit I (COX I), and COX IV were decreased in both injury models and did not recover by 144 h. Immunohistochemical analysis confirmed that COX IV protein was progressively lost in proximal tubules of the kidney cortex after ischemia-reperfusion (I/R). Expression of mitochondrial fission protein Drp1 was elevated after injury in both models, whereas the fusion protein Mfn2 was elevated after glycerol injury but decreased after I/R AKI. LC3-I/II expression revealed that autophagy increased in both injury models at the later time points. Markers of mitochondrial biogenesis, such as PGC-1 alpha and PRC, were elevated in both models. These findings reveal that there is persistent disruption of mitochondrial homeostasis and sustained tubular damage after AKI, even in the presence of mitochondrial recovery signals and improved glomerular filtration.