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Oxidative Stress and Organ Damages

  • Sayoko Ogura
  • Tatsuo ShimosawaEmail author
Mediators, Mechanisms, and Pathways in Tissue Injury (T Fujita, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Mediators, Mechanisms, and Pathways in Tissue Injury

Abstract

Oxidative stress plays a pivotal role in various pathological conditions, including hypertension, pulmonary hypertension, diabetes, and chronic kidney disease, with high levels of oxidative stress in target organs such as the heart, pancreas, kidney, and lung. Oxidative stress is known to activate multiple intracellular signaling, which induces apoptosis or cell overgrowth, leading to organ dysfunction. As such, targeting oxidative stress is thought to be effective in protecting against organ damage, and measuring oxidative stress status may serve as a biomarker in diverse disease states. Several new intrinsic anti-oxidative or pro-oxidative factors have recently been reported, and are potential new targets. In the present review, we focus on diabetes, pulmonary hypertension, and renal dysfunction, and their relation with new targets – adrenomedullin, oxidized LDL, and mineralocorticoid receptor.

Keywords

Oxidative stress Endothelium dysfunction Antioxidants Adrenomedullin LOX-1 Pulmonary hypertension 

Notes

Acknowledgments

This work was supported by JSPS KAKENHI Grant Number 24790863, 26461262.

Compliance with Ethics Guidelines

Conflict of Interest Sayoko Ogura has received a JSPS KAKENHI Grant Number 24790863, 26461262.

Tatsuo Shimosawa has received an honorarium payment from Takeda Pharmaceutical Co., Ltd.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS. Circulation. 2003;108(16):1912–6. doi: 10.1161/01.CIR.0000093660.86242.PubMedGoogle Scholar
  2. 2.
    Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74(6):1141–8.PubMedGoogle Scholar
  3. 3.
    Holland JA, Meyer JW, Chang MM, O’Donnell RW, Johnson DK, Ziegler LM. Thrombin stimulated reactive oxygen species production in cultured human endothelial cells. Endothelium. 1998;6(2):113–21.PubMedGoogle Scholar
  4. 4.
    Marumo T, Schini-Kerth VB, Fisslthaler B, Busse R. Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells. Circulation. 1997;96(7):2361–7.PubMedGoogle Scholar
  5. 5.
    Cardillo C, Kilcoyne CM, Cannon 3rd RO, Quyyumi AA, Panza JA. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension. 1997;30(1 Pt 1):57–63.PubMedGoogle Scholar
  6. 6.
    Hermida N, Balligand JL. Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: the role of statins. Antioxid Redox Signal. 2014;20(8):1216–37. doi: 10.1089/ars.2013.5537.PubMedGoogle Scholar
  7. 7.
    Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293(11):1338–47. doi: 10.1001/jama.293.11.1338.PubMedGoogle Scholar
  8. 8.
    Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res. 1999;85(8):753–66.PubMedGoogle Scholar
  9. 9.
    Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A. 1987;84(9):2995–8.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Li D, Yang B, Mehta JL. Ox-LDL induces apoptosis in human coronary artery endothelial cells: role of PKC, PTK, bcl-2, and Fas. Am J Physiol. 1998;275(2 Pt 2):H568–76.PubMedGoogle Scholar
  11. 11.
    Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386(6620):73–7. doi: 10.1038/386073a0.PubMedGoogle Scholar
  12. 12.
    Nagase M, Ando K, Nagase T, Kaname S, Sawamura T, Fujita T. Redox-sensitive regulation of lox-1 gene expression in vascular endothelium. Biochem Biophys Res Commun. 2001;281(3):720–5. doi: 10.1006/bbrc.2001.4374.PubMedGoogle Scholar
  13. 13.
    Ogura S, Kakino A, Sato Y, Fujita Y, Iwamoto S, Otsui K, et al. Lox-1: the multifunctional receptor underlying cardiovascular dysfunction. Circ J. 2009;73(11):1993–9.PubMedGoogle Scholar
  14. 14.
    Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 1993;192(2):553–60. doi: 10.1006/bbrc.1993.1451.PubMedGoogle Scholar
  15. 15.
    Shimosawa T, Shibagaki Y, Ishibashi K, Kitamura K, Kangawa K, Kato S, et al. Adrenomedullin, an endogenous peptide, counteracts cardiovascular damage. Circulation. 2002;105(1):106–11.PubMedGoogle Scholar
  16. 16.
    Kawai J, Ando K, Tojo A, Shimosawa T, Takahashi K, Onozato ML, et al. Endogenous adrenomedullin protects against vascular response to injury in mice. Circulation. 2004;109(9):1147–53. doi: 10.1161/01.CIR.0000117231.40057.6D.PubMedGoogle Scholar
  17. 17.
    Liu J, Shimosawa T, Matsui H, Meng F, Supowit SC, DiPette DJ, et al. Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity. Am J Physiol Heart Circ Physiol. 2007;292(4):H1714–21. doi: 10.1152/ajpheart.00486.2006.PubMedGoogle Scholar
  18. 18.
    Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima N, et al. Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia. 2004;47(5):794–805. doi: 10.1007/s00125-004-1391-x.PubMedGoogle Scholar
  19. 19.
    Fridlyand LE, Philipson LH. Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes Metab. 2006;8(2):136–45. doi: 10.1111/j.1463-1326.2005.00496.x.PubMedGoogle Scholar
  20. 20.
    Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, et al. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest. 1997;99(1):144–50. doi: 10.1172/JCI119126.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Kaneto H, Xu G, Fujii N, Kim S, Bonner-Weir S, Weir GC. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem. 2002;277(33):30010–8. doi: 10.1074/jbc.M202066200.PubMedGoogle Scholar
  22. 22.
    Kawamori D, Kajimoto Y, Kaneto H, Umayahara Y, Fujitani Y, Miyatsuka T, et al. Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH(2)-terminal kinase. Diabetes. 2003;52(12):2896–904.PubMedGoogle Scholar
  23. 23.
    DeMarco VG, Habibi J, Whaley-Connell AT, Schneider RI, Heller RL, Bosanquet JP, et al. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol. 2008;294(6):H2659–68. doi: 10.1152/ajpheart.00953.2007.PubMedGoogle Scholar
  24. 24.
    Hoshikawa Y, Ono S, Suzuki S, Tanita T, Chida M, Song C, et al. Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol. 2001;90(4):1299–306.PubMedGoogle Scholar
  25. 25.
    Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, et al. Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med. 2004;169(6):764–9. doi: 10.1164/rccm.200301-147OC.PubMedGoogle Scholar
  26. 26.
    Matsui H, Shimosawa T, Itakura K, Guanqun X, Ando K, Fujita T. Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia. Circulation. 2004;109(18):2246–51. doi: 10.1161/01.CIR.0000127950.13380.FD.PubMedGoogle Scholar
  27. 27.
    Nagaya N, Nishikimi T, Uematsu M, Satoh T, Oya H, Kyotani S, et al. Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension. Heart. 2000;84(6):653–8.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Liu JQ, Zelko IN, Erbynn EM, Sham JS, Folz RJ. Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol. 2006;290(1):L2–10. doi: 10.1152/ajplung.00135.2005.PubMedGoogle Scholar
  29. 29.•
    Ogura S, Shimosawa T, Mu S, Sonobe T, Kawakami-Mori F, Wang H, et al. Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor. Am J Physiol Heart Circ Physiol. 2013;305(2):H155–62. doi: 10.1152/ajpheart.00169.2012. In this paper, the role of a receptor of oxidized LDL receptor in pulmonary hypertension is revealed. When the receptor is overexpressed and mice were subjected to hypoxic condition, they developed severe pumonary hypertension, together with increasing oxidative stress via NADPH oxidase activation. This suggests that a receptor for oxidized LDL is one of the receptors to transmit ROS signaling.PubMedGoogle Scholar
  30. 30.
    Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121(24):2661–71. doi: 10.1161/CIRCULATIONAHA.109.916098.PubMedPubMedCentralGoogle Scholar
  31. 31.•
    Dikalov SI, Nazarewicz RR, Bikineyeva A, Hilenski L, Lassegue B, Griendling KK, et al. Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. Antioxid Redox Signal. 2014;20(2):281–94. doi: 10.1089/ars.2012.4918. It has been reported that angiotensin II is an activator for NADPH oxidase and increases ROS in variety of organs. This paper reports that angiotensin II can activate mitochondrial ROS by activating NOX2, mitochondrial K channel. Moreover, mitochondria-derived ROS can further activate cytoplasmic c-Src to activate NADPH oxidase and therefore increase ROS in feed-forward fashion.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Ghasemzadeh N, Patel RS, Eapen DJ, Veledar E, Al Kassem H, Manocha P, et al. Oxidative stress is associated with increased pulmonary artery systolic pressure in humans. Hypertension. 2014. doi: 10.1161/HYPERTENSIONAHA.113.02360.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Kriz W. Glomerular diseases: podocyte hypertrophy mismatch and glomerular disease. Nat Rev Nephrol. 2012;8(11):618–9. doi: 10.1038/nrneph.2012.198.PubMedGoogle Scholar
  34. 34.
    Carney EF. Glomerular disease: Albuminuria inhibits podocyte regeneration. Nat Rev Nephrol. 2013;9(10):554. doi: 10.1038/nrneph.2013.159.PubMedGoogle Scholar
  35. 35.•
    Daehn I, Casalena G, Zhang T, Shi S, Fenninger F, Barasch N, et al. Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J Clin Invest. 2014;124(4):1608–21. doi: 10.1172/JCI71195. This paper reported that reciprocal crosstalk between endothelial cells and podocyte in the kidney plays a pivotal role in glomerular injury. The factors that mediate the crosstalk are TGF beta and endothelin in podocyte and subsequent activation of mitochondrial ROS production in endothelial cells. The data are confirmed both in rodent model and human samples. Targeting mitochondrial ROS can prevent renal damage.PubMedPubMedCentralGoogle Scholar
  36. 36.•
    Miyata T, Takizawa S, van Ypersele de Strihou C. Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets. Am J Physiol Cell Physiol. 2011;300(2):C226–31. doi: 10.1152/ajpcell.00430.2010. This paper is a review on the relationship between hypoxia and ROS in terms of HIF activity and Nrf -1 activity. HIF-1alpha activation can reduce ROS. HIF-1alpha is degradated when it is hydroxylated by PHD. Nrf is also protective against ROS and is degradated by Keap-1. This review includes possible therapeutic compounds that inhibit PHD or increase Nrf-1.PubMedGoogle Scholar
  37. 37.
    Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49(2):355–64. doi: 10.1161/01.HYP.0000255636.11931.a2.PubMedGoogle Scholar
  38. 38.
    Ogihara T, Asano T, Ando K, Chiba Y, Sekine N, Sakoda H, et al. Insulin resistance with enhanced insulin signaling in high-salt diet-fed rats. Diabetes. 2001;50(3):573–83.PubMedGoogle Scholar
  39. 39.
    Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518–22. doi: 10.1038/nature11868.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S, et al. Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension. 2004;43(4):841–8. doi: 10.1161/01.HYP.0000118519.66430.22.PubMedGoogle Scholar
  41. 41.
    Mutoh A, Isshiki M, Fujita T. Aldosterone enhances ligand-stimulated nitric oxide production in endothelial cells. Hypertens Res. 2008;31(9):1811–20. doi: 10.1291/hypres.31.1811.PubMedGoogle Scholar
  42. 42.
    Shibata S, Mu S, Kawarazaki H, Muraoka K, Ishizawa K, Yoshida S, et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121(8):3233–43. doi: 10.1172/JCI43124.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Wang H, Shimosawa T, Matsui H, Kaneko T, Ogura S, Uetake Y, et al. Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions. J Hypertens. 2008;26(7):1453–62. doi: 10.1097/HJH.0b013e328300a232.PubMedGoogle Scholar
  44. 44.
    Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, et al. Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension. 2012;59(2):500–6. doi: 10.1161/HYPERTENSIONAHA.111.185520.PubMedGoogle Scholar
  45. 45.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med. 1999;341(10):709–17. doi: 10.1056/NEJM199909023411001.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of Laboratory Medicine, Department of Pathology and MicrobiologyNihon University School of MedicineTokyoJapan
  2. 2.Department of Clinical Laboratory, Faculty of MedicineUniversity of TokyoTokyoJapan

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