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Augmenter of liver regeneration plays a protective role against hydrogen peroxide-induced oxidative stress in renal proximal tubule cells

Abstract

Oxidative stress plays an important role in cellular destruction. Augmenter of liver regeneration (ALR) is an anti-apoptotic factor that is expressed in all mammalian cells and functions as an anti-oxidant by stimulating the expression of a secretory isoform of clusterin and inhibiting reactive oxygen species (ROS) generation. Previous work from our group showed that ALR expression is upregulated in acute kidney injury (AKI) rats, and recombinant human ALR reduces tubular injury. In the present study, we used small interfering RNA (siRNA) silencing of ALR to examine its role in H2O2 induced mitochondrial injury and apoptosis. Knockdown of ALR increased ROS levels, reduced mitochondrial membrane potential, and increased the release of mitochondrial proteins and the rate of apoptosis in response to H2O2. In addition, the ratio of Bax/Bcl-2 was increased in siRNA/ALR groups treated with H2O2. These data confirm the protective role of ALR against oxidative stress-induced mitochondrial injury and suggest a potential mechanism underlying the protective role of ALR in AKI.

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Abbreviations

ALR:

Augmenter of liver regeneration

AKI:

Acute kidney injury

ROS:

Reactive oxygen species

MMP:

Mitochondrial membrane potential

DCFH-DA:

2-,7-Dichlorofluorescin diacetate

DAPI:

4′,6-Diamidino-2-phenylindole

H2O2 :

Hydrogen peroxide

MTS:

3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt

COX IV:

Cytochrome c oxidase IV

References

  1. Linkermann A, Chen G, Dong G, Kunzendorf U, Krautwald S, Dong Z (2014) Regulated cell death in AKI. J Am Soc Nephrol. doi:10.1681/ASN030262

    PubMed  Google Scholar 

  2. Pathak E, MacMillan-Crow LA, Mayeux PR (2012) Role of mitochondrial oxidants in an in vitro model of sepsis-induced renal injury. J Pharmacol Exp Ther 340:192–201

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Bonventre JV, Yang L (2011) Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 121:4210–4221

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Chan PH (1996) Role of oxidants in ischemic brain damage. Stroke 27(6):1124–1129

    Article  CAS  PubMed  Google Scholar 

  5. Zhang L, Zhao B, Yew DT, Kusiak JW (1997) Processing of Alzheimer’s amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells. Biochem Biophys Res Commun 235(3):845–848

    Article  CAS  PubMed  Google Scholar 

  6. Yu M, Wang J, Li W et al (2008) Proteomic screen defines the hepatocyte nuclear factor 1alpha-binding partners and identifies HMGB1 as a new cofactor of HNF1alpha. Nucleic Acids Res 36:1209–1219

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Liu X, Kim CN, Yang J, Jemmerson R (1996) Induction of apoptotic program in cell free extracts requirement for dATP and cytochrome c. Cell 86:147–157

    Article  CAS  PubMed  Google Scholar 

  8. Richter C (1998) Oxidative stress, mitochondria, and apoptosis. Restor Neurol Neurosci 12:59–62

    CAS  PubMed  Google Scholar 

  9. Hagiya M, Francavilla A, Polimeno L, Ihara I, Sakai H, Seki T (1994) Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene expression of biologically active recombinant ALR and demonstration of tissue distribution. Proc Natl Acad Sci USA 91:8142–8146

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Kallergi E, Kalef-Ezra E, Karagouni-Dalakoura K, Tokatlidis K (2014) Common players in mitochondria biogenesis and neuronal protection against stress-induced apoptosis. Neurochem Res 39:546–555

    Article  CAS  PubMed  Google Scholar 

  11. 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 25:2921–2929

    Article  CAS  PubMed  Google Scholar 

  12. Liao XH, Zhang L, Liu Q, Sun H, Peng CM, Guo H (2012) Augmenter of liver regeneration attenuates tubular cell apoptosis in acute kidney injury in rats:the possible mechanisms. Ren Fail 34:590–599

    Article  CAS  PubMed  Google Scholar 

  13. Farrell SR, Thorpe C (2005) Augmenter of liver regeneration a flavin dependent sulfhydryl oxidase with cytochrome c reductase activity. Biochemistry 44:1532–1541

    Article  CAS  PubMed  Google Scholar 

  14. Gandhi CR (2012) Augmenter of liver regeneration. Fibrogenesis Tissue Repair 5:10

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Banci L, Bertini I, Cefaro C (2010) Molecular chaperone function of Mia40 triggers consecutive induced folding steps of the substrate in mitochondrial protein import. Proc Natl Acad Sci 107:20190–20195

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Bihlmaier K, Mesecke N, Terziyska N, Bien M, Hell K, Herrmann JM (2007) The disulfide relay system of mitochondria is connected to the respiratory chain. J Cell Biol 179:389–395

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Giorda R, Hagiya M, Seki T, Shimonishi M, HarumiSakai A (1996) Analysis of the structure and expression of the augmenter of liver regeneration (ALR) gene. Mol Med 2:97–108

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Polimeno L, Pesetti B, Lisowsky T et al (2009) Protective effect of augmenter of liver regeneration on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Free Radic Res 43:865–875

    Article  PubMed  Google Scholar 

  19. Polimeno L, Pesetti B, De Santis F et al (2012) Decreased expression of the augmenter of liver regeneration results in increased apoptosis and oxidative damage in human-derived glioma cells. Cell Death Dis 3:e289

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Polimeno L, Pesetti B, Annoscia E (2011) Alrp, a survival factor that controls the apoptotic process of regenerating liver after partial hepatectomy in rats. Free Radic Res 45:534–549

    Article  CAS  PubMed  Google Scholar 

  21. Shen Y, Liu Q, Sun H, Li X, Wang N, Guo H (2013) Protective effect of augmenter of liver regeneration on vincristine-induced cell death in Jurkat T leukemia cells. Int Immunopharmacol 17:162–167

    Article  CAS  PubMed  Google Scholar 

  22. Ilowski M, Kleespies A, de Toni EN et al (2011) Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis. Biochem Biophys Res Commun 404:148–152

    Article  CAS  PubMed  Google Scholar 

  23. Satoh T, Sakai N, Enokido Y, Uchiyama Y, Hatanaka H (1996) Free radical-independent protection by nerve growth factor and Bcl-2 of PC12 cells from hydrogen peroxide-triggered apoptosis. J Biochem 120:540–546

    Article  CAS  PubMed  Google Scholar 

  24. Zhang L, Yu H, Sun Y et al (2007) Protective effects of salidroside on ‘-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur J Pharmacol 564:18–25

    Article  CAS  PubMed  Google Scholar 

  25. Cao Y, Fu YL, Yu M et al (2009) Human augmenter of liver regeneration is important for hepatoma cell viability and resistance to radiation-induced oxidative stress. Free Radic Biol Med 47:1057–1066

    Article  CAS  PubMed  Google Scholar 

  26. Hahn P, Lindsten T, Lyubarsky A et al (2004) Deficiency of Bax and Bak protects photoreceptors from light damage in vivo. Cell Death Differ 11:1192–1197

    Article  CAS  PubMed  Google Scholar 

  27. Bae EH, Cho S, Joo SY et al (2011) 4-Hydroxy-2-hexenal-induced apoptosis in human renal proximal tubular epithelial cells. Nephrol Dial Transplant 26:3866–3873

    Article  CAS  PubMed  Google Scholar 

  28. Basile DP, Liapis H, Hammerman MR (1997) Expression of bcl-2 and bax in regenerating rat renal tubules following ischemic injury. Am J Physiol 272:F640–F647

    CAS  PubMed  Google Scholar 

  29. Kluck R, Bossy-Wetzel E, Green D, Newmeyer D (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136

    Article  CAS  PubMed  Google Scholar 

  30. Gross A, Yin XM, Wang K et al (1999) Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 274:1156–1163

    Article  CAS  PubMed  Google Scholar 

  31. Lange H, Lisowsky T, Gerber J (2001) An essential function of the mitochondrial sulfhydryl oxidase Erv1pALR in the maturation of cytosolic FeS proteins. EMBO Rep 2:715–720

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Polimeno L, Capuano F, Marangi L, Margiotta M, Lisowsky T, Ierardi E (2000) The augmenter of liver regeneration induces mitochondrial gene expression in rat liver and enhances oxidative phosphorylation capacity of liver mitochondria. Dig Liver Dis 32:510–517

    Article  CAS  PubMed  Google Scholar 

  33. Hell K (2008) The Erv1-Mia40 disulfide relay system in the intermembrane space of mitochondria. Biochim Biophys Acta 1783:601–609

    Article  CAS  PubMed  Google Scholar 

  34. van Gurp M, Festjens N, van Loo G, Saelens X, Vandenabeele P (2003) Mitochondrial intermembrane proteins in cell death. Biochem Biophys Res Commun 304:487–497

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a Grant from the National Natural Science Foundation of China (39071364) and clinical medicine research special funds of the Chinese medical association (14050370574), and Grants from medical scientific research Projects of Chongqing health and family planning commission (20142031).

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Correspondence to Ling Zhang.

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Xia, N., Yan, Ry., Liu, Q. et al. Augmenter of liver regeneration plays a protective role against hydrogen peroxide-induced oxidative stress in renal proximal tubule cells. Apoptosis 20, 423–432 (2015). https://doi.org/10.1007/s10495-015-1096-2

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  • DOI: https://doi.org/10.1007/s10495-015-1096-2

Keywords

  • Augmenter of liver regeneration
  • Apoptosis
  • Oxidative stress
  • Reactive oxygen species