Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia–reperfusion injury

Abstract

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Chalkias A, Xanthos T (2012) Acute kidney injury. The Lancet 380(9857):1904. https://doi.org/10.1016/s0140-6736(12)62104-7

    Article  Google Scholar 

  2. 2.

    Waikar SS, Liu KD, Chertow GM (2008) Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol 3(3):844–861. https://doi.org/10.2215/CJN.05191107

    Article  PubMed  Google Scholar 

  3. 3.

    Lo LJ, Go AS, Chertow GM, McCulloch CE, Fan D, Ordonez JD, Hsu CY (2009) Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease. Kidney Int 76(8):893–899. https://doi.org/10.1038/ki.2009.289

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Verma SK, Molitoris BA (2015) Renal endothelial injury and microvascular dysfunction in acute kidney injury. Semin Nephrol 35(1):96–107. https://doi.org/10.1016/j.semnephrol.2015.01.010

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Kim J, Jung KJ, Park KM (2010) Reactive oxygen species differently regulate renal tubular epithelial and interstitial cell proliferation after ischemia and reperfusion injury. Am J Physiol Renal Physiol 298(5):F1118–F1129. https://doi.org/10.1152/ajprenal.00701.2009

    CAS  Article  PubMed  Google Scholar 

  6. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    O’Connor PM (2006) Renal oxygen delivery: matching delivery to metabolic demand. Clin Exp Pharmacol Physiol 33(10):961–967. https://doi.org/10.1111/j.1440-1681.2006.04475.x

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Bhargava P, Schnellmann RG (2017) Mitochondrial energetics in the kidney. Nat Rev Nephrol 13(10):629–646. https://doi.org/10.1038/nrneph.2017.107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 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

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Stallons LJ, Whitaker RM, Schnellmann RG (2014) Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis. Toxicol Lett 224(3):326–332. https://doi.org/10.1016/j.toxlet.2013.11.014

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Funk JA, Schnellmann RG (2012) Persistent disruption of mitochondrial homeostasis after acute kidney injury. Am J Physiol Renal Physiol 302(7):F853–F864. https://doi.org/10.1152/ajprenal.00035.2011

    Article  PubMed  Google Scholar 

  12. 12.

    Peterson YK, Cameron RB, Wills LP, Trager RE, Lindsey CC, Beeson CC, Schnellmann RG (2013) beta2-Adrenoceptor agonists in the regulation of mitochondrial biogenesis. Bioorg Med Chem Lett 23(19):5376–5381. https://doi.org/10.1016/j.bmcl.2013.07.052

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Gupta P, Venugopal SK (2018) Augmenter of liver regeneration: a key protein in liver regeneration and pathophysiology. Hepatol Res 48(8):587–596. https://doi.org/10.1111/hepr.13077

    Article  PubMed  Google Scholar 

  14. 14.

    Balogh T, Szarka A (2015) [ALR, the multifunctional protein]. Orv Hetil 156(13):503–509. https://doi.org/10.1556/OH.2015.30119

    Article  PubMed  Google Scholar 

  15. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Mordas A, Tokatlidis K (2015) The MIA pathway: a key regulator of mitochondrial oxidative protein folding and biogenesis. Acc Chem Res 48(8):2191–2199. https://doi.org/10.1021/acs.accounts.5b00150

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Weng J, Li W, Jia X, An W (2017) Alleviation of ischemia–reperfusion injury in liver steatosis by augmenter of liver regeneration is attributed to antioxidation and preservation of mitochondria. Transplantation 101(10):2340–2348. https://doi.org/10.1097/TP.0000000000001874

    Article  Google Scholar 

  18. 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

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Xia N, Yan RY, Liu Q, Liao XH, Sun H, Guo H, Zhang L (2015) Augmenter of liver regeneration plays a protective role against hydrogen peroxide-induced oxidative stress in renal proximal tubule cells. Apoptosis 20(4):423–432. https://doi.org/10.1007/s10495-015-1096-2

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Liao XH, Zhang L, Liu Q, Sun H, Peng CM, Guo H (2010) Augmenter of liver regeneration protects kidneys from ischaemia/reperfusion injury in rats. Nephrol Dial Transplant 25(9):2921–2929. https://doi.org/10.1093/ndt/gfq151

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Liao XH, Zhang L, Tang XP, Liu Q, Sun H (2009) Expression of augmenter of liver regeneration in rats with gentamicin-induced acute renal failure and its protective effect on kidney. Ren Fail 31(10):946–955. https://doi.org/10.3109/08860220903216154

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Khwaja A (2012) KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 120(4):c179–184. https://doi.org/10.1159/000339789

    Article  PubMed  Google Scholar 

  23. 23.

    Aydin Z, van Zonneveld AJ, de Fijter JW, Rabelink TJ (2007) New horizons in prevention and treatment of ischaemic injury to kidney transplants. Nephrol Dial Transplant 22(2):342–346. https://doi.org/10.1093/ndt/gfl690

    Article  PubMed  Google Scholar 

  24. 24.

    Zweier JL, Talukder MA (2006) The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 70(2):181–190. https://doi.org/10.1016/j.cardiores.2006.02.025

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Sharfuddin AA, Molitoris BA (2011) Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 7(4):189–200. https://doi.org/10.1038/nrneph.2011.16

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Yan R, Li Y, Zhang L, Xia N, Liu Q, Sun H, Guo H (2015) Augmenter of liver regeneration attenuates inflammation of renal ischemia/reperfusion injury through the NF-kappa B pathway in rats. Int Urol Nephrol 47(5):861–868. https://doi.org/10.1007/s11255-015-0954-8

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Wu CK, Dailey TA, Dailey HA, Wang BC, Rose JP (2003) The crystal structure of augmenter of liver regeneration: a mammalian FAD-dependent sulfhydryl oxidase. Protein Sci 12(5):1109–1118. https://doi.org/10.1110/ps.0238103

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Sztolsztener ME, Brewinska A, Guiard B, Chacinska A (2013) Disulfide bond formation: sulfhydryl oxidase ALR controls mitochondrial biogenesis of human MIA40. Traffic 14(3):309–320. https://doi.org/10.1111/tra.12030

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Funk JA, Schnellmann RG (2013) Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1alpha activation following ischemia-reperfusion injury. Toxicol Appl Pharmacol 273(2):345–354. https://doi.org/10.1016/j.taap.2013.09.026

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Lynn EG, Stevens MV, Wong RP, Carabenciov D, Jacobson J, Murphy E, Sack MN (2010) Transient upregulation of PGC-1α diminishes cardiac ischemia tolerance via upregulation of ANT1. J Mol Cell Cardiol 49(4):693–698. https://doi.org/10.1016/j.yjmcc.2010.06.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 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

    CAS  Article  PubMed  Google Scholar 

  32. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Scarpulla RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88(2):611–638. https://doi.org/10.1152/physrev.00025.2007

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87(1):99–163. https://doi.org/10.1152/physrev.00013.2006

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Reel B, Guzeloglu M, Bagriyanik A, Atmaca S, Aykut K, Albayrak G, Hazan E (2013) The effects of PPAR-gamma agonist pioglitazone on renal ischemia/reperfusion injury in rats. J Surg Res 182(1):176–184. https://doi.org/10.1016/j.jss.2012.08.020

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Tang BL (2016) Sirt1 and the mitochondria. Mol Cells 39(2):87–95. https://doi.org/10.14348/molcells.2016.2318

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Xiao-hui Liao.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest or financial interests to declare.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • Augmenter of liver regeneration
  • Mitochondrial biogenesis
  • Ischemia–reperfusion injury
  • Reactive oxygen species