Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia–reperfusion injury
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.
KeywordsAugmenter of liver regeneration Mitochondrial biogenesis Ischemia–reperfusion injury Reactive oxygen species
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).
Compliance with ethical standards
Conflict of interest
The authors have no conflicts of interest or financial interests to declare.
- 6.Wang Z, Ying Z, Bosy-Westphal A, Zhang J, Schautz B, Later W, Heymsfield SB, Muller MJ (2010) Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. Am J Clin Nutr 92(6):1369–1377. https://doi.org/10.3945/ajcn.2010.29885 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Plotnikov EY, Kazachenko AV, Vyssokikh MY, Vasileva AK, Tcvirkun DV, Isaev NK, Kirpatovsky VI, Zorov DB (2007) The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney. Kidney Int 72(12):1493–1502. https://doi.org/10.1038/sj.ki.5002568 CrossRefPubMedGoogle Scholar
- 15.Ozer HK, Dlouhy AC, Thornton JD, Hu J, Liu Y, Barycki JJ, Balk J, Outten CE (2015) Cytosolic Fe-S cluster protein maturation and iron regulation are independent of the mitochondrial Erv1/Mia40 import system. J Biol Chem 290(46):27829–27840. https://doi.org/10.1074/jbc.M115.682179 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Gandhi CR, Chaillet JR, Nalesnik MA, Kumar S, Dangi A, Demetris AJ, Ferrell R, Wu T, Divanovic S, Stankeiwicz T, Shaffer B, Stolz DB, Harvey SA, Wang J, Starzl TE (2015) Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice. Gastroenterology 148(2):379–391 e374. https://doi.org/10.1053/j.gastro.2014.10.008 CrossRefPubMedGoogle Scholar
- 31.Jiang WG, Douglas-Jones A, Mansel RE (2003) Expression of peroxisome-proliferator activated receptor-gamma (PPARgamma) and the PPARgamma co-activator, PGC-1, in human breast cancer correlates with clinical outcomes. Int J Cancer 106(5):752–757. https://doi.org/10.1002/ijc.11302 CrossRefPubMedGoogle Scholar
- 32.Choi HI, Kim HJ, Park JS, Kim IJ, Bae EH, Ma SK, Kim SW (2017) PGC-1alpha attenuates hydrogen peroxide-induced apoptotic cell death by upregulating Nrf-2 via GSK3beta inactivation mediated by activated p38 in HK-2 Cells. Sci Rep 7(1):4319. https://doi.org/10.1038/s41598-017-04593-w CrossRefPubMedPubMedCentralGoogle Scholar