Skip to main content
SpringerLink
Log in

Coenzyme Q10 protects renal proximal tubule cells against nicotine-induced apoptosis through induction of p66shc-dependent antioxidant responses

  • The many ways of apoptotic cell death
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Chronic nicotine exposure (via smoking, E-cigarettes) increases oxidative stress in the kidney that sensitizes it to additional injury in experimental models and in the renal patient. The pro-apoptotic p66shc protein—via serine36 phosphorylation that facilitates its mitochondrial translocation and therein cytochrome c binding—generates oxidative stress that leads to injury of renal proximal tubule cells during chronic nicotine exposure. Coenzyme Q10—a clinically safe antioxidant—has been used against nicotine/smoke extract-associated oxidative stress in various non-renal cells. This study explored the anti-oxidant/anti-apoptotic effect of Coenzyme Q10 on nicotine-induced oxidative stress and its impact on p66shc in cultured rat renal proximal tubule cells (NRK52E). We studied the anti-oxidant effect of 10 µM Coenzyme Q10 using various mutants of the p66shc gene and also determined the induction of selected anti-oxidant entities (antioxidant response element, promoter of the manganese superoxide dismutase gene) in reporter luciferase assay during oxidative stress induced by 200 µM nicotine. Our studies revealed that Coenzyme Q10 strongly inhibits nicotine-mediated production of reactive oxygen species and consequent apoptosis that requires serine36 phosphorylation but not mitochondrial translocation/cytochrome c binding of p66shc. While both nicotine and Coenzyme Q10 stimulates the p66shc promoter, only nicotine exposure results in mitochondrial translocation of p66shc. In contrast, the Coenzyme Q10-stimulated and non-mitochondrial p66shc activates the anti-oxidant manganese superoxide dismutase promoter via the antioxidant response elements and hence, rescues cells from nicotine-induced oxidative stress and consequent apoptosis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ARE:

Antioxidant response element

CHAPS:

3-((3-Cholamidopropyl) dimethylammonio)-1-propanesulfonate

CKD:

Chronic kidney disease

CoQ10:

Coenzyme Q10

DCFDA:

2′,7′-Dichlorofluorescein-diacetate

HBSS:

Hank’s balanced salt solution

MnSOD:

Manganese superoxide dismutase

NIC:

Nicotine

Nrf2:

NF-E2 DNA binding protein

p66shc :

Src homology2α/collagen homology protein isoform protein

ROS:

Reactive oxygen species

siNrf2:

Short interfering RNA for Nrf2

shMnSOD:

Short-hairpin MnSOD

shp66shc:

Short-hairpin-p66shc plasmid

References

  1. Baggio B (2000) Ischemic renal disease: impact of cardiovascular risk factors and smoking. Contrib Nephrol 130:68–74

    Article  CAS  PubMed  Google Scholar 

  2. Gambaro G, Verlato F, Budakovic A et al (1998) Renal impairment in chronic cigarette smokers. J Am Soc Nephrol 9:562–567

    CAS  PubMed  Google Scholar 

  3. Orth SR, Hallan SI (2008) Smoking: a risk factor for progression of chronic kidney disease and for cardiovascular morbidity and mortality in renal patients–absence of evidence or evidence of absence? Clin J Am Soc Nephrol 3:226–236

    Article  PubMed  Google Scholar 

  4. Arany I, Grifoni S, Clark JS, Csongradi E, Maric C, Juncos LA (2011) Chronic nicotine exposure exacerbates acute renal ischemic injury. Am J Physiol Renal Physiol 301:F125–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. EL-S IA, Afifi AM, Shouman AE, EL-S AK (2004) Effects of smoking and lead exposure on proximal tubular integrity among Egyptian industrial workers. Arch Med Res 35:59–65

    Article  Google Scholar 

  6. Hultberg B, Isaksson A, Brattstrom L, Israelsson B (1992) Elevated urinary excretion of beta-hexosaminidase in smokers. Eur J Clin Chem Clin Biochem 30:131–133

    CAS  PubMed  Google Scholar 

  7. Cigremis Y, Turkoz Y, Akgoz M, Sozmen M (2004) The effects of chronic exposure to ethanol and cigarette smoke on the level of reduced glutathione and malondialdehyde in rat kidney. Urol Res 32:213–218

    Article  CAS  PubMed  Google Scholar 

  8. Cigremis Y, Turkoz Y, Tuzcu M et al (2006) The effects of chronic exposure to ethanol and cigarette smoke on the formation of peroxynitrite, level of nitric oxide, xanthine oxidase and myeloperoxidase activities in rat kidney. Mol Cell Biochem 291:127–138

    Article  CAS  PubMed  Google Scholar 

  9. Cobanoglu B, Ozercan IH, Ozercan MR, Yalcin O (2007) The effect of inhaling thinner and/or cigarette smoke on rat kidneys. Inhal Toxicol 19:303–308

    Article  CAS  PubMed  Google Scholar 

  10. Czekaj P, Palasz A, Lebda-Wyborny T et al (2002) Morphological changes in lungs, placenta, liver and kidneys of pregnant rats exposed to cigarette smoke. Int Arch Occup Environ Health 75:S27–35

    Article  CAS  PubMed  Google Scholar 

  11. Hukkanen J, Jacob P III, Benowitz NL (2005) Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57:79–115

    Article  CAS  PubMed  Google Scholar 

  12. Kim KY, Lee YJ, Chung BC, Hong J, Jung BH (2010) Relations between toxicity and altered tissue distribution and urinary excretion of nicotine, cotinine, and hydroxycotinine after chronic oral administration of nicotine in rats. Drug Chem Toxicol 33:166–172

    Article  CAS  PubMed  Google Scholar 

  13. Zeidler R, Albermann K, Lang S (2007) Nicotine and apoptosis. Apoptosis 12:1927–1943

    Article  CAS  PubMed  Google Scholar 

  14. Kim CS, Choi JS, Joo SY et al (2016) Nicotine-induced apoptosis in human renal proximal tubular epithelial cells. PLoS One 11:e0152591

    Article  PubMed  PubMed Central  Google Scholar 

  15. Giorgio M, Migliaccio E, Orsini F et al (2005) Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122:221–233

    Article  CAS  PubMed  Google Scholar 

  16. Pellegrini M, Pacini S, Baldari CT (2005) p66SHC: the apoptotic side of Shc proteins. Apoptosis 10:13–18

    Article  CAS  PubMed  Google Scholar 

  17. Arany I, Clark J, Reed DK, Juncos LA (2013) Chronic nicotine exposure augments renal oxidative stress and injury through transcriptional activation of p66shc. Nephrol Dialysis Transplant 28:1417–1425

    Article  CAS  Google Scholar 

  18. Zhang ZW, Xu XC, Liu T, Yuan S (2016) Mitochondrion-permeable antioxidants to treat ROS-burst-mediated acute diseases. Ox Med Cell Long 2016:6859523

    Google Scholar 

  19. Fatima S, Al-Mohaimeed N, Al-Shaikh Y et al (2016) Combined treatment of epigallocatechin gallate and Coenzyme Q10 attenuates cisplatin-induced nephrotoxicity via suppression of oxidative/nitrosative stress, inflammation and cellular damage. Food Chem Toxicol 94:213–220

    Article  CAS  PubMed  Google Scholar 

  20. Conklin KA (2005) Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity. Integ Cancer Ther 4:110–130

    Article  CAS  Google Scholar 

  21. Bruin JE, Woynillowicz AK, Hettinga BP et al (2012) Maternal antioxidants prevent beta-cell apoptosis and promote formation of dual hormone-expressing endocrine cells in male offspring following fetal and neonatal nicotine exposure. J Diabetes 4:297–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kaisar MA, Prasad S, Cucullo L (2015) Protecting the BBB endothelium against cigarette smoke-induced oxidative stress using popular antioxidants: are they really beneficial? Brain Res 1627:90–100

    Article  PubMed  PubMed Central  Google Scholar 

  23. Figuero E, Soory M, Cerero R, Bascones A (2006) Oxidant/antioxidant interactions of nicotine, Coenzyme Q10, Pycnogenol and phytoestrogens in oral periosteal fibroblasts and MG63 osteoblasts. Steroids 71:1062–1072

    Article  CAS  PubMed  Google Scholar 

  24. Arany I, Faisal A, Clark JS, Vera T, Baliga R, Nagamine Y (2010) p66SHC-mediated mitochondrial dysfunction in renal proximal tubule cells during oxidative injury. Am J Physiol Renal Physiol 298:F1214–F1221

    Article  CAS  PubMed  Google Scholar 

  25. Arany I, Megyesi JK, Kaneto H, Price PM, Safirstein RL (2004) Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. Am J Physiol Renal Physiol 287:F543–549

    Article  CAS  PubMed  Google Scholar 

  26. Arany I, Faisal A, Nagamine Y, Safirstein RL (2008) p66shc inhibits pro-survival epidermal growth factor receptor/ERK signaling during severe oxidative stress in mouse renal proximal tubule cells. J Biol Chem 283:6110–6117

    Article  CAS  PubMed  Google Scholar 

  27. Arany I, Hall S, Reed DK, Dixit M (2016) The pro-oxidant gene p66shc increases nicotine exposure-induced lipotoxic oxidative stress in renal proximal tubule cells. Mol Med Rep 14:2771–2777

    CAS  PubMed  Google Scholar 

  28. Kim CS, Jung SB, Naqvi A et al (2008) p53 impairs endothelium-dependent vasomotor function through transcriptional upregulation of p66shc. Circ Res 103:1441–1450

    Article  CAS  PubMed  Google Scholar 

  29. Essers MA, Weijzen S, de Vries-Smits AM et al (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. Embo J 23:4802–4812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kannan K, Jain SK (2000) Oxidative stress and apoptosis. Pathophysiology 7:153–163

    Article  CAS  PubMed  Google Scholar 

  31. Tian N, Rose RA, Jordan S, Dwyer TM, Hughson MD, Manning RD Jr (2006) N-Acetylcysteine improves renal dysfunction, ameliorates kidney damage and decreases blood pressure in salt-sensitive hypertension. J Hypertens 24:2263–2270

    Article  CAS  PubMed  Google Scholar 

  32. Arany I, Faisal A, Clark JS, Vera T, Baliga R, Nagamine Y (2010) p66SHC-mediated mitochondrial dysfunction in renal proximal tubule cells during oxidative injury. Am J Physiol Renal Physiol 298:F1214–1221

    Article  CAS  PubMed  Google Scholar 

  33. Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Huang XS, Chen HP, Yu HH, Yan YF, Liao ZP, Huang QR (2014) Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for hypoxic preconditioning-mediated delayed cardioprotection. Mol Cell Biochem 385:33–41

    Article  CAS  PubMed  Google Scholar 

  35. Ojeda N, Hall S, Lasley CJ, Rudsenske B, Dixit M, Arany I (2016) Prenatal nicotine exposure augments renal oxidative stress in embryos of pregnant rats with reduced uterine perfusion pressure. In vivo (Athens, Greece) 30:219–224

    CAS  Google Scholar 

  36. Orth SR, Viedt C, Ritz E (2001) Adverse effects of smoking in the renal patient. Tohoku J Exp Med 194:1–15

    Article  CAS  PubMed  Google Scholar 

  37. Sener G, Sehirli AO, Ipci Y, Cetinel S, Cikler E, Gedik N (2005) Chronic nicotine toxicity is prevented by aqueous garlic extract. Plant Foods Hum Nutr 60:77–86

    Article  PubMed  Google Scholar 

  38. Sener G, Sehirli O, Ipci Y et al (2005) Protective effects of taurine against nicotine-induced oxidative damage of rat urinary bladder and kidney. Pharmacology 74:37–44

    Article  CAS  PubMed  Google Scholar 

  39. Bruin JE, Petre MA, Lehman MA et al (2008) Maternal nicotine exposure increases oxidative stress in the offspring. Free Radic Biol Med 44:1919–1925

    Article  CAS  PubMed  Google Scholar 

  40. Cormier A, Morin C, Zini R, Tillement JP, Lagrue G (2001) In vitro effects of nicotine on mitochondrial respiration and superoxide anion generation. Brain Res 900:72–79

    Article  CAS  PubMed  Google Scholar 

  41. Galimov ER. (2010) The role of p66shc in oxidative stress and apoptosis. Acta Naturae 2:44–51

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Gertz M, Steegborn C (2010) The Lifespan-regulator p66Shc in mitochondria: redox enzyme or redox sensor? Antioxid Redox Signal 13:1417–1428

    Article  CAS  PubMed  Google Scholar 

  43. Pellegrini M, Baldari CT (2009) Apoptosis and oxidative stress-related diseases: the p66Shc connection. Curr Mol Med 9:392–398

    Article  CAS  PubMed  Google Scholar 

  44. Garrido-Maraver J, Cordero MD, Oropesa-Avila M et al (2014) Clinical applications of coenzyme Q10. Front Biosci 19:619–633

    Article  CAS  Google Scholar 

  45. Abitagaoglu S, Akinci SB, Saricaoglu F et al (2015) Effect of coenzyme Q10 on organ damage in sepsis. Bratisl Lek Listy 116:433–439

    CAS  PubMed  Google Scholar 

  46. Maheshwari RA, Balaraman R, Sen AK, Seth AK (2014) Effect of coenzyme Q10 alone and its combination with metformin on streptozotocin-nicotinamide-induced diabetic nephropathy in rats. Ind J Pharmacol 46:627–632

    Article  CAS  Google Scholar 

  47. Fatima S, Al-Mohaimeed N, Arjumand S, Banu N, Al-Jameil N, Al-Shaikh Y (2015) Effect of pre- and post-combined multidoses of epigallocatechin gallate and coenzyme Q10 on cisplatin-induced oxidative stress in rat kidney. J Biochem Mol Toxicol 29:91–97

    Article  CAS  PubMed  Google Scholar 

  48. Li L, Du J, Lian Y et al (2016) Protective effects of Coenzyme Q10 against hydrogen peroxide-induced oxidative stress in PC12 Cell: the role of Nrf2 and antioxidant enzymes. Cell Mol Neurobiol 36:103–111

    Article  CAS  PubMed  Google Scholar 

  49. Choi HK, Pokharel YR, Lim SC et al (2009) Inhibition of liver fibrosis by solubilized coenzyme Q10: role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression. Toxicol Appl Pharmacol 240:377–384

    Article  CAS  PubMed  Google Scholar 

  50. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW (2010) When NRF2 talks, who’s listening? Antioxid Redox Signal 13:1649–1663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Orsini F, Migliaccio E, Moroni M et al (2004) The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem 279:25689–25695

    Article  CAS  PubMed  Google Scholar 

  52. Miyazawa M, Tsuji Y (2014) Evidence for a novel antioxidant function and isoform-specific regulation of the human p66Shc gene. Mol Biol Cell 25:2116–2127

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ventura A, Luzi L, Pacini S, Baldari CT, Pelicci PG (2002) The p66Shc longevity gene is silenced through epigenetic modifications of an alternative promoter. J Biol Chem 277:22370–22376

    Article  CAS  PubMed  Google Scholar 

  54. Premkumar VG, Yuvaraj S, Shanthi P, Sachdanandam P (2008) Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy. Brit J Nutr 100:1179–1182

    Article  CAS  PubMed  Google Scholar 

  55. Pinton P, Rimessi A, Marchi S et al (2007) Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science 315:659–663

    Article  CAS  PubMed  Google Scholar 

  56. Mai Y, Higashi T, Terada K et al (2012) Nicotine- and tar-free cigarette smoke extract induces cell injury via intracellular Ca2+-dependent subtype-specific protein kinase C activation. J Pharmacol Sci 120:310–314

    Article  CAS  PubMed  Google Scholar 

  57. Cho YA, Jue SS, Bae WJ et al (2015) PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses. J Dent Res 94:371–380

    Article  PubMed  PubMed Central  Google Scholar 

  58. Tsuneki H, Sekizaki N, Suzuki T et al (2007) Coenzyme Q10 prevents high glucose-induced oxidative stress in human umbilical vein endothelial cells. Eur J Pharmacol 566:1–10

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Department of Pediatrics, University of Mississippi Medical Center and the Bower Foundation. The Authors wish to thank Dr. Irani for the p66shc-promoter luciferase plasmid and to Dr. Burgering for the MnSOD-promoter luciferase plasmid.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Research Wing Room R116/B, 2500 N. State St., Jackson, MS, 39216, USA

    Istvan Arany, Anthony Carter, Samuel Hall & Mehul Dixit

  2. Department of Medicine, Division of Nephrology, University of Mississippi Medical Center, Jackson, MS, USA

    Tibor Fulop

Authors
  1. Istvan Arany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samuel Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tibor Fulop
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mehul Dixit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Istvan Arany.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arany, I., Carter, A., Hall, S. et al. Coenzyme Q10 protects renal proximal tubule cells against nicotine-induced apoptosis through induction of p66shc-dependent antioxidant responses. Apoptosis 22, 220–228 (2017). https://doi.org/10.1007/s10495-016-1309-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-016-1309-3

Keywords

Search

Navigation