Mitochondria are the center of energy metabolism in the cell and the preferential target of various toxicants and ischemic injury. Renal ischemia–reperfusion (I/R) injury triggers proximal tubule injury and the mitochondria are believed to be the primary subcellular target of I/R injury. The promotion of mitochondrial biogenesis (MB) is critical for the prevention I/R injury. The results of our previous study showed that augmenter of liver regeneration (ALR) has anti-apoptotic and anti-oxidant functions. However, the modulatory mechanism of ALR remains unclear and warrants further investigation. To gain further insight into the role of ALR in MB, human kidney (HK)-2 cells were treated with lentiviruses carrying ALR short interfering RNA (siRNA) and a model of hypoxia reoxygenation (H/R) injury in vitro was created. We observed that knockdown of ALR promoted apoptosis of renal tubular cells and aggravated mitochondrial injury, as evidenced by the decrease in the mitochondrial respiratory proteins adenosine triphosphate (ATP) synthase subunit β, cytochrome c oxidase subunit 1, and nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) beta subcomplex 8. Meanwhile, the production of reactive oxygen species was increased and ATP levels were decreased significantly in HK-2 cells, as compared with the siRNA/control group (p < 0.05). In addition, the mitochondrial DNA copy number and membrane potential were markedly decreased. Furthermore, critical transcriptional regulators of MB (i.e., peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, mitochondrial transcription factor A, sirtuin-1, and nuclear respiratory factor-1) were depleted in the siRNA/ALR group. Taken together, these findings unveil essential roles of ALR in the inhibition of renal tubular cell apoptosis and attenuation of mitochondrial dysfunction by promoting MB in AKI.
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This work was supported by grants from the National Natural Science Foundation of China (81873604, 30971364), the Natural Science Foundation Project of CQ CSTC (cstc2015jcyjA10069), the Medical Scientific Research Projects of the Chongqing Health and Family Planning Commission (20142031), and the Fund for Fostering Talent in Scientific Research of Chongqing Medical University (201404).
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Huang, Ll., Long, Rt., Jiang, Gp. et al. Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia–reperfusion injury. Apoptosis 23, 695–706 (2018). https://doi.org/10.1007/s10495-018-1487-2
- Augmenter of liver regeneration
- Mitochondrial biogenesis
- Ischemia–reperfusion injury
- Reactive oxygen species