ROS in Atherosclerotic Renovascular Disease

  • Xiang-Yang Zhu
  • Lilach O. LermanEmail author
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


The hallmark of atherosclerotic renovascular disease (ARVD) is activation of the renin-angiotensin-aldosterone system, in which Ang II induces NAD(P)H oxidase-derived reactive oxygen species (ROS). Renovascular hypertension may also induce oscillatory shear stress, which is linked to increased ROS production with consequent oxidative damage. Induction of these signaling cascades leads to expression of pro-inflammatory mediators, cell apoptosis, and modification of extracellular matrix, eventuating in endothelial dysfunction, glomerulosclerosis, microvascular rarefaction, and tissue fibrosis. ROS-mediated kidney injury, primarily in the stenotic and also in the contralateral kidney, impair renal function. Intervention with antioxidants has the potential to improve renal function in experimental setting but failed to translate into clinical outcome. Angiotensin converting enzyme inhibitor/angiotensin receptor blockers have showed potential of attenuation of oxidative stress while improving clinical outcome. Stem cells combined with percutaneous transluminal renal angioplasty has promising results in experimental ARVD and translational studies are urgently needed in this area.


Atherosclerosis Kidney Renovascular disease Angiotensin Reactive oxygen species Inflammation Fibrosis Hypertension Apoptosis Shear stress 


  1. 1.
    Hansen KJ, Edwards MS, Craven TE, Cherr GS, Jackson SA, Appel RG, et al. Prevalence of renovascular disease in the elderly: a population-based study. J Vasc Surg. 2002;36:443–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Keddis MT, Garovic VD, Bailey KR, Wood CM, Raissian Y, Grande JP. Ischaemic nephropathy secondary to atherosclerotic renal artery stenosis: clinical and histopathological correlates. Nephrol Dial Transplant. 2010;25:3615–22.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154–69.PubMedCrossRefGoogle Scholar
  4. 4.
    Goldblatt H, Lynch J, Hanzal RF, Summerville WW. Studies on experimental hypertension : I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med. 1934;59:347–79.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Lerman LO, Nath KA, Rodriguez-Porcel M, Krier JD, Schwartz RS, Napoli C, et al. Increased oxidative stress in experimental renovascular hypertension. Hypertension. 2001;37:541–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Lerman LO, Schwartz RS, Grande JP, Sheedy PF, Romero JC. Noninvasive evaluation of a novel swine model of renal artery stenosis. J Am Soc Nephrol. 1999;10:1455–65.PubMedGoogle Scholar
  7. 7.
    Vasilev T, Kiprov D, Puchlev A, Todorova L. Plasma renin activity in patients with renovascular hypertension. Cor Vasa. 1978;20:35–43.PubMedGoogle Scholar
  8. 8.
    Chade AR, Rodriguez-Porcel M, Grande JP, Krier JD, Lerman A, Romero JC, et al. Distinct renal injury in early atherosclerosis and renovascular disease. Circulation. 2002;106:1165–71.PubMedCrossRefGoogle Scholar
  9. 9.
    Hartono SP, Knudsen BE, Zubair AS, Nath KA, Textor SJ, Lerman LO, et al. Redox signaling is an early event in the pathogenesis of renovascular hypertension. Int J Mol Sci. 2013;14:18640–56.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Marks LS, Maxwell MH. Tigerstedt and the discovery of renin. An historical note. Hypertension. 1979;1:384–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Braun-Menendez E, Page IH. Suggested revision of nomenclature—angiotensin. Science. 1958;127:242.PubMedCrossRefGoogle Scholar
  12. 12.
    Skeggs Jr LT, Kahn JR, Shumway NP. The purification of hypertensin II. J Exp Med. 1956;103:301–7.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Fyhrquist F, Saijonmaa O. Renin-angiotensin system revisited. J Intern Med. 2008;264:224–36.PubMedCrossRefGoogle Scholar
  14. 14.
    Aroor AR, Demarco VG, Jia G, Sun Z, Nistala R, Meininger GA, et al. The role of tissue renin-angiotensin-aldosterone system in the development of endothelial dysfunction and arterial stiffness. Front Endocrinol. 2013;4:161.CrossRefGoogle Scholar
  15. 15.
    Ikemoto F, Song GB, Tominaga M, Kanayama Y, Yamamoto K. Angiotensin-converting enzyme in the rat kidney. Activity, distribution, and response to angiotensin-converting enzyme inhibitors. Nephron. 1990;55 Suppl 1:3–9.PubMedGoogle Scholar
  16. 16.
    Kim SM, Kim YG, Jeong KH, Lee SH, Lee TW, Ihm CG, et al. Angiotensin II-induced mitochondrial Nox4 is a major endogenous source of oxidative stress in kidney tubular cells. PLoS One. 2012;7, e39739.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Zhou A, Carrell RW, Murphy MP, Wei Z, Yan Y, Stanley PL, et al. A redox switch in angiotensinogen modulates angiotensin release. Nature. 2010;468:108–11.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Ozawa Y, Kobori H, Suzaki Y, Navar LG. Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusions. Am J Physiol Renal Physiol. 2007;292:F330–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Li L, Huang L, Sung SS, Vergis AL, Rosin DL, Rose Jr CE, et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int. 2008;74:1526–37.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Li P, Garcia GE, Xia Y, Wu W, Gersch C, Park PW, et al. Blocking of monocyte chemoattractant protein-1 during tubulointerstitial nephritis resulted in delayed neutrophil clearance. Am J Pathol. 2005;167:637–49.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Alvarez A, Cerda-Nicolas M, Naim Abu Nabah Y, Mata M, Issekutz AC, Panes J, et al. Direct evidence of leukocyte adhesion in arterioles by angiotensin II. Blood. 2004;104:402–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Phillips MI, Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs. 2002;3:569–77.PubMedGoogle Scholar
  24. 24.
    Kranzhofer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kubler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999;19:1623–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Ni W, Kitamoto S, Ishibashi M, Usui M, Inoue S, Hiasa K, et al. Monocyte chemoattractant protein-1 is an essential inflammatory mediator in angiotensin II-induced progression of established atherosclerosis in hypercholesterolemic mice. Arterioscler Thromb Vasc Biol. 2004;24:534–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Moreno-Manzano V, Ishikawa Y, Lucio-Cazana J, Kitamura M. Selective involvement of superoxide anion, but not downstream compounds hydrogen peroxide and peroxynitrite, in tumor necrosis factor-alpha-induced apoptosis of rat mesangial cells. J Biol Chem. 2000;275:12684–91.PubMedCrossRefGoogle Scholar
  27. 27.
    Rajamohan SB, Raghuraman G, Prabhakar NR, Kumar GK. NADPH oxidase-derived H(2)O(2) contributes to angiotensin II-induced aldosterone synthesis in human and rat adrenal cortical cells. Antioxid Redox Signal. 2012;17:445–59.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Stouffer GA, Pathak A, Rojas M. Unilateral renal artery stenosis causes a chronic vascular inflammatory response in ApoE−/− mice. Trans Am Clin Climatol Assoc. 2010;121:252–64. 264-6.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Schleicher E, Friess U. Oxidative stress, AGE, and atherosclerosis. Kidney Int Suppl. 2007;S17–26.Google Scholar
  30. 30.
    Basta G, Lazzerini G, Del Turco S, Ratto GM, Schmidt AM, De Caterina R. At least 2 distinct pathways generating reactive oxygen species mediate vascular cell adhesion molecule-1 induction by advanced glycation end products. Arterioscler Thromb Vasc Biol. 2005;25:1401–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Gao X, Zhang H, Schmidt AM, Zhang C. AGE/RAGE produces endothelial dysfunction in coronary arterioles in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 2008;295:H491–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Johnson KJ, Weinberg JM. Postischemic renal injury due to oxygen radicals. Curr Opin Nephrol Hypertens. 1993;2:625–35.PubMedCrossRefGoogle Scholar
  33. 33.
    Kaminski KA, Bonda TA, Korecki J, Musial WJ. Oxidative stress and neutrophil activation—the two keystones of ischemia/reperfusion injury. Int J Cardiol. 2002;86:41–59.PubMedCrossRefGoogle Scholar
  34. 34.
    Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. Clin Immunol. 2009;130:41–50.PubMedCrossRefGoogle Scholar
  35. 35.
    Liu H, Liu S, Li Y, Wang X, Xue W, Ge G, et al. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. PLoS One. 2012;7, e34608.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Wei Q, Bhatt K, He HZ, Mi QS, Haase VH, Dong Z. Targeted deletion of Dicer from proximal tubules protects against renal ischemia-reperfusion injury. J Am Soc Nephrol. 2010;21:756–61.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Cantaluppi V, Gatti S, Medica D, Figliolini F, Bruno S, Deregibus MC, et al. Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int. 2012;82:412–27.PubMedCrossRefGoogle Scholar
  38. 38.
    Lubas A, Zelichowski G, Prochnicka A, Wisniewska M, Wankowicz Z. Renal autoregulation in medical therapy of renovascular hypertension. Arch Med Sci. 2010;6:912–8.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Textor SC, Lerman L. Renovascular hypertension and ischemic nephropathy. Am J Hypertens. 2010;23:1159–69.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Goldsmith SR. Interactions between the sympathetic nervous system and the RAAS in heart failure. Curr Heart Fail Rep. 2004;1:45–50.PubMedCrossRefGoogle Scholar
  41. 41.
    Oeckler RA, Kaminski PM, Wolin MS. Stretch enhances contraction of bovine coronary arteries via an NAD(P)H oxidase-mediated activation of the extracellular signal-regulated kinase mitogen-activated protein kinase cascade. Circ Res. 2003;92:23–31.PubMedCrossRefGoogle Scholar
  42. 42.
    Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med. 2002;346:1954–62.PubMedCrossRefGoogle Scholar
  43. 43.
    Gobe GC, Axelsen RA, Searle JW. Cellular events in experimental unilateral ischemic renal atrophy and in regeneration after contralateral nephrectomy. Lab Invest. 1990;63:770–9.PubMedGoogle Scholar
  44. 44.
    Grone HJ, Warnecke E, Olbricht CJ. Characteristics of renal tubular atrophy in experimental renovascular hypertension: a model of kidney hibernation. Nephron. 1996;72:243–52.PubMedCrossRefGoogle Scholar
  45. 45.
    Lieberthal W, Triaca V, Koh JS, Pagano PJ, Levine JS. Role of superoxide in apoptosis induced by growth factor withdrawal. Am J Physiol. 1998;275:F691–702.PubMedGoogle Scholar
  46. 46.
    Kim J, Jung KJ, Park KM. Reactive oxygen species differently regulate renal tubular epithelial and interstitial cell proliferation after ischemia and reperfusion injury. Am J Physiol Renal Physiol. 2010;298:F1118–29.PubMedCrossRefGoogle Scholar
  47. 47.
    Ding W, Yang L, Zhang M, Gu Y. Reactive oxygen species-mediated endoplasmic reticulum stress contributes to aldosterone-induced apoptosis in tubular epithelial cells. Biochem Biophys Res Commun. 2012;418:451–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Oien AH, Aukland K. A mathematical analysis of the myogenic hypothesis with special reference to autoregulation of renal blood flow. Circ Res. 1983;52:241–52.PubMedCrossRefGoogle Scholar
  49. 49.
    Hope A, Clausen G, Rosivall L. Total and local renal blood flow and filtration in the rat during reduced renal arterial blood pressure. Acta Physiol Scand. 1981;113:455–63.PubMedCrossRefGoogle Scholar
  50. 50.
    Chade AR, Zhu XY, Grande JP, Krier JD, Lerman A, Lerman LO. Simvastatin abates development of renal fibrosis in experimental renovascular disease. J Hypertens. 2008;26:1651–60.PubMedCrossRefGoogle Scholar
  51. 51.
    Wright JR, Duggal A, Thomas R, Reeve R, Roberts IS, Kalra PA. Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: implications for renal functional outcome in atherosclerotic renovascular disease. Nephrol Dial Transplant. 2001;16:765–70.PubMedCrossRefGoogle Scholar
  52. 52.
    Johnson RJ, Couser WG, Chi EY, Adler S, Klebanoff SJ. New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system. J Clin Invest. 1987;79:1379–87.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Rahman MM, Varghese Z, Fuller BJ, Moorhead JF. Renal vasoconstriction induced by oxidized LDL is inhibited by scavengers of reactive oxygen species and L-arginine. Clin Nephrol. 1999;51:98–107.PubMedGoogle Scholar
  54. 54.
    Chade AR, Rodriguez-Porcel M, Herrmann J, Zhu X, Grande JP, Napoli C, et al. Antioxidant intervention blunts renal injury in experimental renovascular disease. J Am Soc Nephrol. 2004;15:958–66.PubMedCrossRefGoogle Scholar
  55. 55.
    Gloviczki ML, Keddis MT, Garovic VD, Friedman H, Herrmann S, McKusick MA, et al. TGF expression and macrophage accumulation in atherosclerotic renal artery stenosis. Clin J Am Soc Nephrol. 2013;8:546–53.PubMedCrossRefGoogle Scholar
  56. 56.
    Urbieta-Caceres VH, Zhu XY, Jordan KL, Tang H, Textor K, Lerman A, et al. Selective improvement in renal function preserved remote myocardial microvascular integrity and architecture in experimental renovascular disease. Atherosclerosis. 2012;221:350–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Warner GM, Cheng J, Knudsen BE, Gray CE, Deibel A, Juskewitch JE, et al. Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension. Am J Physiol Renal Physiol. 2012;302:F1455–64.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Iglesias De La Cruz MC, Ruiz-Torres P, Alcami J, Diez-Marques L, Ortega-Velazquez R, Chen S, et al. Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells. Kidney Int. 2001;59:87–95.PubMedCrossRefGoogle Scholar
  59. 59.
    Chade AR, Rodriguez-Porcel M, Grande JP, Zhu X, Sica V, Napoli C, et al. Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis. Arterioscler Thromb Vasc Biol. 2003;23:1295–301.PubMedCrossRefGoogle Scholar
  60. 60.
    Ceron CS, Rizzi E, Guimaraes DA, Martins-Oliveira A, Cau SB, Ramos J, et al. Time course involvement of matrix metalloproteinases in the vascular alterations of renovascular hypertension. Matrix Biol. 2012;31:261–70.PubMedCrossRefGoogle Scholar
  61. 61.
    Pialoux V, Mounier R, Brown AD, Steinback CD, Rawling JM, Poulin MJ. Relationship between oxidative stress and HIF-1 alpha mRNA during sustained hypoxia in humans. Free Radic Biol Med. 2009;46:321–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Richard DE, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem. 2000;275:26765–71.PubMedGoogle Scholar
  63. 63.
    Irwin DC, McCord JM, Nozik-Grayck E, Beckly G, Foreman B, Sullivan T, et al. A potential role for reactive oxygen species and the HIF-1alpha-VEGF pathway in hypoxia-induced pulmonary vascular leak. Free Radic Biol Med. 2009;47:55–61.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Zhu XY, Chade AR, Rodriguez-Porcel M, Bentley MD, Ritman EL, Lerman A, et al. Cortical microvascular remodeling in the stenotic kidney: role of increased oxidative stress. Arterioscler Thromb Vasc Biol. 2004;24:1854–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Fujii H, Nakamura S, Kuroda S, Yoshihara F, Nakahama H, Inenaga T, et al. Relationship between renal artery stenosis and intrarenal damage in autopsy subjects with stroke. Nephrol Dial Transplant. 2006;21:113–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Cheng J, Zhou W, Warner GM, Knudsen BE, Garovic VD, Gray CE, et al. Temporal analysis of signaling pathways activated in a murine model of two-kidney, one-clip hypertension. Am J Physiol Renal Physiol. 2009;297:F1055–68.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Johnson RJ, Segal MS, Srinivas T, Ejaz A, Mu W, Roncal C, et al. Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link? J Am Soc Nephrol. 2005;16:1909–19.PubMedCrossRefGoogle Scholar
  68. 68.
    Hayashi K, Epstein M, Saruta T. Altered myogenic responsiveness of the renal microvasculature in experimental hypertension. J Hypertens. 1996;14:1387–401.PubMedCrossRefGoogle Scholar
  69. 69.
    Liu R, Carretero OA, Ren Y, Garvin JL. Increased intracellular pH at the macula densa activates nNOS during tubuloglomerular feedback. Kidney Int. 2005;67:1837–43.PubMedCrossRefGoogle Scholar
  70. 70.
    Welch WJ, Mendonca M, Aslam S, Wilcox CS. Roles of oxidative stress and AT1 receptors in renal hemodynamics and oxygenation in the postclipped 2 K,1C kidney. Hypertension. 2003;41:692–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Endo Y, Arima S, Yaoita H, Tsunoda K, Omata K, Ito S. Vasodilation mediated by angiotensin II type 2 receptor is impaired in afferent arterioles of young spontaneously hypertensive rats. J Vasc Res. 1998;35:421–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Bochkov VN, Tkachuk VA, Hahn AW, Bernhardt J, Buhler FR, Resink TJ. Concerted effects of lipoproteins and angiotensin II on signal transduction processes in vascular smooth muscle cells. Arterioscler Thromb. 1993;13:1261–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Izuhara Y, Nangaku M, Inagi R, Tominaga N, Aizawa T, Kurokawa K, et al. Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. J Am Soc Nephrol. 2005;16:3631–41.PubMedCrossRefGoogle Scholar
  74. 74.
    Jang HS, Kim JI, Kim J, Na YK, Park JW, Park KM. Bone marrow derived cells and reactive oxygen species in hypertrophy of contralateral kidney of transient unilateral renal ischemia-induced mouse. Free Radic Res. 2012;46:903–11.PubMedCrossRefGoogle Scholar
  75. 75.
    Moller JC. Proximal tubules in long-term compensatory renal growth. Quantitative light- and electron-microscopic analyses. APMIS Suppl. 1988;4:82–6.PubMedGoogle Scholar
  76. 76.
    Miller SB, Rogers SA, Estes CE, Hammerman MR. Increased distal nephron EGF content and altered distribution of peptide in compensatory renal hypertrophy. Am J Physiol. 1992;262:F1032–8.PubMedGoogle Scholar
  77. 77.
    Sinuani I, Averbukh Z, Gitelman I, Rapoport MJ, Sandbank J, Albeck M, et al. Mesangial cells initiate compensatory renal tubular hypertrophy via IL-10-induced TGF-beta secretion: effect of the immunomodulator AS101 on this process. Am J Physiol Renal Physiol. 2006;291:F384–94.PubMedCrossRefGoogle Scholar
  78. 78.
    Gentle ME, Shi S, Daehn I, Zhang T, Qi H, Yu L, et al. Epithelial cell TGFbeta signaling induces acute tubular injury and interstitial inflammation. J Am Soc Nephrol. 2013;24:787–99.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Zhang H, Jiang Z, Chang J, Li X, Zhu H, Lan HY, et al. Role of NAD(P)H oxidase in transforming growth factor-beta1-induced monocyte chemoattractant protein-1 and interleukin-6 expression in rat renal tubular epithelial cells. Nephrology. 2009;14:302–10.PubMedCrossRefGoogle Scholar
  80. 80.
    Bae EH, Cho S, Joo SY, Ma SK, Kim SH, Lee J, et al. 4-Hydroxy-2-hexenal-induced apoptosis in human renal proximal tubular epithelial cells. Nephrol Dial Transplant. 2011;26:3866–73.PubMedCrossRefGoogle Scholar
  81. 81.
    Kimura G, London GM, Safar ME, Kuramochi M, Omae T. Glomerular hypertension in renovascular hypertensive patients. Kidney Int. 1991;39:966–72.PubMedCrossRefGoogle Scholar
  82. 82.
    Alchi B, Shirasaki A, Narita I, Nishi S, Ueno M, Saeki T, et al. Renovascular hypertension: a unique cause of unilateral focal segmental glomerulosclerosis. Hypertens Res. 2006;29:203–7.PubMedCrossRefGoogle Scholar
  83. 83.
    Bhowmik D, Dash SC, Jain D, Agarwal SK, Tiwari SC, Dinda AK. Renal artery stenosis and focal segmental glomerulosclerosis in the contralateral kidney. Nephrol Dial Transplant. 1998;13:1562–4.PubMedCrossRefGoogle Scholar
  84. 84.
    Ubara Y, Hara S, Katori H, Yamada A, Morii H. Renovascular hypertension may cause nephrotic range proteinuria and focal glomerulosclerosis in contralateral kidney. Clin Nephrol. 1997;48:220–3.PubMedGoogle Scholar
  85. 85.
    Paravicini TM, Touyz RM. Redox signaling in hypertension. Cardiovasc Res. 2006;71:247–58.PubMedCrossRefGoogle Scholar
  86. 86.
    Zhu XY, Chade AR, Krier JD, Daghini E, Lavi R, Guglielmotti A, et al. The chemokine monocyte chemoattractant protein-1 contributes to renal dysfunction in swine renovascular hypertension. J Hypertens. 2009;27:2063–73.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Brezniceanu ML, Liu F, Wei CC, Chenier I, Godin N, Zhang SL, et al. Attenuation of interstitial fibrosis and tubular apoptosis in db/db transgenic mice overexpressing catalase in renal proximal tubular cells. Diabetes. 2008;57:451–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Rizzi E, Guimaraes DA, Ceron CS, Prado CM, Pinheiro LC, Martins-Oliveira A, et al. Beta-adrenergic blockers exert antioxidant effects, reduce matrix metalloproteinase activity, and improve renovascular hypertension-induced cardiac hypertrophy. Free Radic Biol Med. 2014;73C:308–17.CrossRefGoogle Scholar
  89. 89.
    Castro MM, Rizzi E, Rodrigues GJ, Ceron CS, Bendhack LM, Gerlach RF, et al. Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension. Free Radic Biol Med. 2009;46:1298–307.PubMedCrossRefGoogle Scholar
  90. 90.
    Miravete M, Dissard R, Klein J, Gonzalez J, Caubet C, Pecher C, et al. Renal tubular fluid shear stress facilitates monocyte activation toward inflammatory macrophages. Am J Physiol Renal Physiol. 2012;302:F1409–17.PubMedCrossRefGoogle Scholar
  91. 91.
    Grabias BM, Konstantopoulos K. Notch4-dependent antagonism of canonical TGF-beta1 signaling defines unique temporal fluctuations of SMAD3 activity in sheared proximal tubular epithelial cells. Am J Physiol Renal Physiol. 2013;305:F123–33.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Anderson WP, Kett MM, Evans RG, Alcorn D. Pre-glomerular structural changes in the renal vasculature in hypertension. Blood Press Suppl. 1995;2:74–80.PubMedGoogle Scholar
  93. 93.
    Jung O, Schreiber JG, Geiger H, Pedrazzini T, Busse R, Brandes RP. gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension. Circulation. 2004;109:1795–801.PubMedCrossRefGoogle Scholar
  94. 94.
    Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, et al. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension. 2002;40:511–5.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.PubMedCrossRefGoogle Scholar
  96. 96.
    Zinkevich NS, Gutterman DD. ROS-induced ROS release in vascular biology: redox-redox signaling. Am J Physiol Heart Circ Physiol. 2011;301:H647–53.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Su Q, Qin DN, Wang FX, Ren J, Li HB, Zhang M, et al. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension. Toxicol Appl Pharmacol. 2014;276:115–20.PubMedCrossRefGoogle Scholar
  98. 98.
    Zimmerman MC, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, et al. Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res. 2002;91:1038–45.PubMedCrossRefGoogle Scholar
  99. 99.
    Cui W, Matsuno K, Iwata K, Ibi M, Katsuyama M, Kakehi T, et al. NADPH oxidase isoforms and anti-hypertensive effects of atorvastatin demonstrated in two animal models. J Pharmacol Sci. 2009;111:260–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension. 2004;44:248–52.PubMedCrossRefGoogle Scholar
  101. 101.
    Costa CA, Amaral TA, Carvalho LC, Ognibene DT, da Silva AF, Moss MB, et al. Antioxidant treatment with tempol and apocynin prevents endothelial dysfunction and development of renovascular hypertension. Am J Hypertens. 2009;22:1242–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Schnackenberg CG, Wilcox CS. Two-week administration of tempol attenuates both hypertension and renal excretion of 8-Iso prostaglandin f2alpha. Hypertension. 1999;33:424–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood pressure and renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic: role of nitric oxide. Hypertension. 1998;32:59–64.PubMedCrossRefGoogle Scholar
  104. 104.
    Elks CM, Reed SD, Mariappan N, Shukitt-Hale B, Joseph JA, Ingram DK, et al. A blueberry-enriched diet attenuates nephropathy in a rat model of hypertension via reduction in oxidative stress. PLoS One. 2011;6, e24028.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Salonen RM, Nyyssonen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen TH, et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation. 2003;107:947–53.PubMedCrossRefGoogle Scholar
  106. 106.
    Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154–60.PubMedCrossRefGoogle Scholar
  107. 107.
    Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Wang X, Skelley L, Wang B, Mejia A, Sapozhnikov V, Sun Z. AAV-based RNAi silencing of NADPH oxidase gp91(phox) attenuates cold-induced cardiovascular dysfunction. Hum Gene Ther. 2012;23:1016–26.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Eirin A, Ebrahimi B, Zhang X, Zhu XY, Woollard JR, He Q, et al. Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease. Cardiovasc Res. 2014;103:461–72.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Eirin A, Li Z, Zhang X, Krier JD, Woollard JR, Zhu XY, et al. A mitochondrial permeability transition pore inhibitor improves renal outcomes after revascularization in experimental atherosclerotic renal artery stenosis. Hypertension. 2012;60:1242–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Nickenig G, Ostergren J, Struijker-Boudier H. Clinical evidence for the cardiovascular benefits of angiotensin receptor blockers. J Renin Angiotensin Aldosterone Syst. 2006;7 Suppl 1:S1–7.PubMedCrossRefGoogle Scholar
  112. 112.
    Stafylas PC, Sarafidis PA, Grekas DM, Lasaridis AN. A cost-effectiveness analysis of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in diabetic nephropathy. J Clin Hypertens. 2007;9:751–9.CrossRefGoogle Scholar
  113. 113.
    Tullis MJ, Caps MT, Zierler RE, Bergelin RO, Polissar N, Cantwell-Gab K, et al. Blood pressure, antihypertensive medication, and atherosclerotic renal artery stenosis. Am J Kidney Dis. 1999;33:675–81.PubMedCrossRefGoogle Scholar
  114. 114.
    Losito A, Gaburri M, Errico R, Parente B, Cao PG. Survival of patients with renovascular disease and ACE inhibition. Clin Nephrol. 1999;52:339–43.PubMedGoogle Scholar
  115. 115.
    Losito A, Errico R, Santirosi P, Lupattelli T, Scalera GB, Lupattelli L. Long-term follow-up of atherosclerotic renovascular disease. Beneficial effect of ACE inhibition. Nephrol Dial Transplant. 2005;20:1604–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Hackam DG, Duong-Hua ML, Mamdani M, Li P, Tobe SW, Spence JD, et al. Angiotensin inhibition in renovascular disease: a population-based cohort study. Am Heart J. 2008;156:549–55.PubMedCrossRefGoogle Scholar
  117. 117.
    Chrysochou C, Foley RN, Young JF, Khavandi K, Cheung CM, Kalra PA. Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease. Nephrol Dial Transplant. 2012;27:1403–9.PubMedCrossRefGoogle Scholar
  118. 118.
    Onuigbo MA, Onuigbo NT. Worsening renal failure in older chronic kidney disease patients with renal artery stenosis concurrently on renin angiotensin aldosterone system blockade: a prospective 50-month Mayo-Health-System clinic analysis. QJM. 2008;101:519–27.PubMedCrossRefGoogle Scholar
  119. 119.
    Dincer Y, Sekercioglu N, Pekpak M, Gunes KN, Akcay T. Assessment of DNA oxidation and antioxidant activity in hypertensive patients with chronic kidney disease. Ren Fail. 2008;30:1006–11.PubMedCrossRefGoogle Scholar
  120. 120.
    Davies MG, Saad WE, Bismuth JX, Naoum JJ, Peden EK, Lumsden AB. Endovascular revascularization of renal artery stenosis in the solitary functioning kidney. J Vasc Surg. 2009;49:953–60.PubMedCrossRefGoogle Scholar
  121. 121.
    Ziakka S, Ursu M, Poulikakos D, Papadopoulos C, Karakasis F, Kaperonis N, et al. Predictive factors and therapeutic approach of renovascular disease: four years’ follow-up. Ren Fail. 2008;30:965–70.PubMedCrossRefGoogle Scholar
  122. 122.
    Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370:13–22.PubMedCrossRefGoogle Scholar
  123. 123.
    Eirin A, Zhu XY, Urbieta-Caceres VH, Grande JP, Lerman A, Textor SC, et al. Persistent kidney dysfunction in swine renal artery stenosis correlates with outer cortical microvascular remodeling. Ren Physiol. 2011;300:F1394–401.CrossRefGoogle Scholar
  124. 124.
    Eirin A, Ebrahimi B, Zhang X, Zhu XY, Tang H, Crane JA, et al. Changes in glomerular filtration rate after renal revascularization correlate with microvascular hemodynamics and inflammation in Swine renal artery stenosis. Circ Cardiovasc Interv. 2012;5:720–8.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Saad A, Herrmann SM, Crane J, Glockner JF, McKusick MA, Misra S, et al. Stent revascularization restores cortical blood flow and reverses tissue hypoxia in atherosclerotic renal artery stenosis but fails to reverse inflammatory pathways or glomerular filtration rate. Circ Cardiovasc Interv. 2013;6:428–35.PubMedCrossRefGoogle Scholar
  126. 126.
    Wheatley K, Ives N, Gray R, Kalra PA, Moss JG, Baigent C, et al. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med. 2009;361:1953–62.PubMedCrossRefGoogle Scholar
  127. 127.
    Eirin A, Zhu XY, Krier JD, Tang H, Jordan KL, Grande JP, et al. Adipose tissue-derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cells. 2012;30:1030–41.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Zhuo W, Liao L, Xu T, Wu W, Yang S, Tan J. Mesenchymal stem cells ameliorate ischemia-reperfusion-induced renal dysfunction by improving the antioxidant/oxidant balance in the ischemic kidney. Urol Int. 2011;86:191–6.PubMedCrossRefGoogle Scholar
  129. 129.
    Chen YT, Sun CK, Lin YC, Chang LT, Chen YL, Tsai TH, et al. Adipose-derived mesenchymal stem cell protects kidneys against ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med. 2011;9:51.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Hagiwara M, Shen B, Chao L, Chao J. Kallikrein-modified mesenchymal stem cell implantation provides enhanced protection against acute ischemic kidney injury by inhibiting apoptosis and inflammation. Hum Gene Ther. 2008;19:807–19.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Division of Nephrology and HypertensionMayo ClinicRochesterUSA

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