Abstract
Background and objectives: Acute kidney injury (AKI) is a clinical condition associated with a degree of morbidity and mortality despite supportive care, and ischemia/reperfusion injury (I/R) is one of the main causes of AKI. The pathophysiology of I/R injury is a complex cascade of events including the release of free oxygen radicals followed by damage to proteins, lipids, mitochondria, and deranged tissue oxygenation. In this study, we investigated whether the antioxidant ascorbic acid would be able to largely prevent oxidative stress and consequently, reduce I/R-related injury to the kidneys in terms of oxygenation, inflammation, and renal failure. Materials and methods: Rats were divided into three groups (n = 6/group): (1) a time control group; (2) a group subjected to renal ischemia for 60 min by high aortic occlusion followed by 2 h of reperfusion (I/R); and (3) a group subjected to I/R and treated with an i.v. 100 mg/kg bolus ascorbic acid 15 min before ischemia and continuous infusion of 50 mg/kg/hour for 2 h during reperfusion (I/R + AA). We measured renal tissue oxidative stress, microvascular oxygenation, renal oxygen delivery and consumption, and renal expression of inflammatory and injury markers. Results: We demonstrated that aortic clamping and release resulted in increased oxidative stress and inflammation that was associated with a significant fall in systemic and renal hemodynamics and oxygenation parameters. The treatment of ascorbic acid completely abrogated oxidative stress and inflammatory parameters. However, it only partly improved microcirculatory oxygenation and was without any effect on anuria. Conclusion: The ascorbic acid treatment partly improves microcirculatory oxygenation and prevents oxidative stress without restoring urine output in a severe I/R model of AKI.
References
1. Rabb H, Wang Z, NemotoT, Hotchkiss J, Yokota N, Soleimani M. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int 2003; 63: 600-6.10.1046/j.1523-1755.2003.00753.xSearch in Google Scholar PubMed
2. Evans RG, Ince C, Joles JA, Smith DW, May CN, O’Connor PM, et al. Haemodynamic influences on kidney oxygenation: clinical implications of integrative physiology. Clin Exp Pharmacol Physiol 2013; 40: 106-22.10.1111/1440-1681.12031Search in Google Scholar PubMed
3. Le Dorze M, Legrand M, Payen D, Ince C. The role of the microcirculation in acute kidney injury. Curr Opin Crit Care 2009; 15: 503-8.10.1097/MCC.0b013e328332f6cfSearch in Google Scholar PubMed
4. Singh P, Ricksten SE, Bragadottir G, Redfors B, Nordquist L. Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. Clin Exp Pharmacol Physiol 2013; 40: 138-47.10.1111/1440-1681.12036Search in Google Scholar PubMed PubMed Central
5. Evans RG, Eppel GA, Michaels S, Burke SL, Nematbakhsh M, Head GA, et al. Multiple mechanisms act to maintain kidney oxygenation during renal ischemia in anesthetized rabbits. Am J Physiol Renal Physiol 2010; 298: F1235-43.10.1152/ajprenal.00647.2009Search in Google Scholar PubMed
6. Evans RG, Gardiner BS, Smith DW, O’Connor PM. Intrarenal oxygenation: Unique challenges and the biophysical basis of homeostasis. Am J Physiol Renal Physiol 2008; 295: F1259-70.10.1152/ajprenal.90230.2008Search in Google Scholar PubMed
7. Warner L, Gomez SI, Bolterman R, Haas JA, Bentley MD, Lerman LO, et al. Regional decreases in renal oxygenation during graded acute renal arterial stenosis: a case for renal ischemia. Am J Physiol Regul Integr Comp Physiol 2009; 296: R67-71.10.1152/ajpregu.90677.2008Search in Google Scholar PubMed PubMed Central
8. Abdelkader A, Ho J, Ow CP, Eppel GA, Rajapakse NW, Schlaich MP, et al. Renal oxygenation in acute renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 2014; 306: F1026-38.10.1152/ajprenal.00281.2013Search in Google Scholar PubMed
9. Legrand M, Almac E, Mik EG, Johannes T, Kandil A, Bezemer R, et al. L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats. Am J Physiol Renal Physiol 2009; 296: F1109-17.10.1152/ajprenal.90371.2008Search in Google Scholar PubMed
10. Legrand M, Kandil A, Payen D, Ince C. Effects of sepiapterin infusion on renal oxygenation and early acute renal injury after suprarenal aortic clamping in rats. J Cardiovasc Pharmacol 2011; 58: 192-8.10.1097/FJC.0b013e31821f8ec3Search in Google Scholar PubMed
11. Parrino PE, Laubach VE, Gaughen JR, Shockey KS, Wattsman TA, King RC, et al. Inhibition of inducible nitric oxide synthase after myocardial ischemia increases coronary flow. Ann Thorac Surg 1998; 66:733.10.1016/S0003-4975(98)00605-5Search in Google Scholar
12. Koksel O, Ozdulger A, Aytacoglu B, Polat A, Sucu N, Yildirim C, et al. The influence of iloprost on acute lung injury induced by hind limb ischemia-reperfusion in rats. Pulm Pharmacol Ther 2005; 18: 235-41.10.1016/j.pupt.2004.12.005Search in Google Scholar PubMed
13. Grace PA. Ischemia-reperfusion injury. Br J Surg 1994; 81: 637.10.1002/bjs.1800810504Search in Google Scholar PubMed
14. Noiri E, Nakao A, Uchida K, Tsukahara H, Ohno M, Fujita T, et al. Oxidative and nitrosative stress in acute renal ischemia. Am J Physiol Renal Physiol 2001; 281: F948.10.1152/ajprenal.2001.281.5.F948Search in Google Scholar PubMed
15. Versteilen AM, Di Maggio F, Leemreis JR, Groeneveld AB, Musters RJ, Sipkema P. Molecular mechanisms of acute renal failure following ischemia/reperfusion. Int J Artif Organs 2004; 27: 1019.10.1177/039139880402701203Search in Google Scholar PubMed
16. Lum H, Roebuck KA. Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol 2001; 280: C719.10.1152/ajpcell.2001.280.4.C719Search in Google Scholar PubMed
17. Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am SocNephrol 2003; 14: 2199.Search in Google Scholar
18. Legrand M, Ince C, Mik E, Johannes T, Payen D. Renal hypoxia and dysoxia following reperfusion of the ischemic kidney. Mol Med 2008; 14: 502-16.10.2119/2008-00006.LegrandSearch in Google Scholar PubMed PubMed Central
19. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 2001; 281: F887-99.10.1152/ajprenal.0050.2001Search in Google Scholar
20. Molitoris BA, Sandoval R, Sutton TA. Endothelial injury and dysfunction in ischemic acute renal failure. Crit Care Med 2002; 30: S235-40.10.1097/00003246-200205001-00011Search in Google Scholar PubMed
21. Brodsky SV, Yamamoto T, Tada T, Kim B, Chen J, Kajiya F, et al. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol 2002; 282: F1140-9.10.1152/ajprenal.00329.2001Search in Google Scholar PubMed
22. Sutton TA, Mang HE, Campos SB, Sandoval RM, Yoder MC, Molitoris BA. Injury of the renal microvascular endothelium alters barrier function after ischemia. Am J Physiol Renal Physiol 2003; 285: F191-8.10.1152/ajprenal.00042.2003Search in Google Scholar PubMed
23. Goode HF, Webster NR, Howdle PD, Leek JP, Lodge JP, Sammi AS, et al. Reperfusion injury, antioxidants and hemodynamics during orthotopic liver transplantation. Hepatology 1994; 19: 354.10.1002/hep.1840190213Search in Google Scholar
24. Xia Y, Khatchikian G, Zweier JY. Adenosin deaminase inhibition prevents free radical mediated injury in the postischemic heart. J Biol Chem 1996; 271: 10096.10.1074/jbc.271.17.10096Search in Google Scholar PubMed
25. Cherubini A, Polidori MC, Bregnocchi M, Pezzuto S, Cecchetti R, Ingegni T, et al. Antioxidant profile and early outcome in stroke patients. Stroke 2000; 31: 2295.10.1161/01.STR.31.10.2295Search in Google Scholar PubMed
26. Sadat U, Usman A, Gillard JH, Boyle JR. Does ascorbic acid protect against contrast induced- acute kidney injury in patients undergoing coronary angiography - a systematic review with meta-analysis of randomized controlled trials. J Am Coll Cardiol 2013; 62: 2167-75.10.1016/j.jacc.2013.07.065Search in Google Scholar PubMed
27. Zuurbier CJ, Emons VM, Ince C. Hemodynamics of anesthetized ventilated mouse models: aspects of anesthetics, fluid support, and strain. Am J Physiol Heart Circ Physiol 2002; 282: H2099-105.10.1152/ajpheart.01002.2001Search in Google Scholar PubMed
28. Johannes T, Mik EG, Ince C. Dual-wavelength phosphorimetry for determination of cortical and subcortical microvascular oxygenation in rat kidney. J Appl Physiol 2006; 100: 1301-10.10.1152/japplphysiol.01315.2005Search in Google Scholar PubMed
29. Mik EG, Johannes T, Zuurbier CJ, Heinen A, Houben-Weerts JH, Balestra GM, et al. In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique. Biophys J 2008; 95: 3977-90.10.1529/biophysj.107.126094Search in Google Scholar PubMed PubMed Central
30. Bezemer R, Faber DJ, Almac E, Kalkman J, Legrand M, Heger M, et al. Evaluation of multi-exponential curve fitting analysis of oxygenquenched phosphorescence decay traces for recovering microvascular oxygen tension histograms. Med Biol Eng Comput 2010; 48: 1233-42.10.1007/s11517-010-0698-7Search in Google Scholar PubMed PubMed Central
31. Demirci C, Gargili A, Kandil A, Cetinkaya H, Uyaner I, Boynuegri B, et al. Inhibition of inducible nitric oxide synthase in murinevisceral larva migrans: effects on lung and liver damage. Chin J Physiol 2006;49: 326-34.Search in Google Scholar
32. O’Connor PM, Kett MM, Anderson WP, Evans RG. Renal medullary tissue oxygenation is dependent on both cortical and medullary blood flow. Am J Physiol Renal Physiol 2006; 290: F688-94.10.1152/ajprenal.00275.2005Search in Google Scholar PubMed
33. Johannes T, Mik EG, Nohe B, Unertl KE, Ince C. Acute decrease in renal microvascular PO2 during acute normovolemichemodilution.Am J Physiol Renal Physiol 2007; 292: F796-803.10.1152/ajprenal.00206.2006Search in Google Scholar
34. Cowley AW Jr, Mori T, Mattson D, Zou AP. Role of renal NO production in the regulation of medullary blood flow. Am J Physiol Regul Integr Comp Physiol 2003; 284: R1355-69.10.1152/ajpregu.00701.2002Search in Google Scholar
35. Adler S, Huang H, Loke KE, Xu X, Tada H, Laumas A, et al. Endothelial nitric oxide synthase plays an essential role in regulation of renal oxygen consumption by NO. Am J Physiol Renal Physiol 2001; 280: F838 -43.10.1152/ajprenal.2001.280.5.F838Search in Google Scholar
36. Laycock SK, Vogel T, Forfia PR, Tuzman J, Xu X, Ochoa M, et al. Role of nitric oxide in the control of renal oxygen consumption and the regulation of chemical work in the kidney. Circ Res 1998; 82: 1263-1271.10.1161/01.RES.82.12.1263Search in Google Scholar
37. Karaman A, Turkmen E, Gursul C, Tas E, Fadillioglu E. Prevention of renal ischemia/reperfusion-induced injury in rats by leflunomide. Int J Urol 2006; 13: 1434-41.10.1111/j.1442-2042.2006.01592.xSearch in Google Scholar
38. Tyml K, Li F, Wilson JX. Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med 2005; 33: 1823-8.10.1097/01.CCM.0000172548.34622.DESearch in Google Scholar
39. Wang P, Zhu Q, Wu N, Siow YL, Aukema HOK. Tyrosol attenuates ischemia-reperfusion-induced kidney injury via inhibition of inducible nitric oxide synthase. J Agric Food Chem 2013; 17; 61: 3669-75.10.1021/jf400227uSearch in Google Scholar
40. Szabó C, Módis K. Pathophysiological roles ofperoxynitritein circulatory shock. Shock 34: 4-14.10.1097/SHK.0b013e3181e7e9baSearch in Google Scholar
41. Gullans SR, Hebert SC. Metabolic basis of ion transport. In: Brenner and Rector’s The Kidney (5th ed.), edited by Brenner BM. Philadelphia, PA: WB Saunders, 1996: 211-246.Search in Google Scholar
42. Eschwege P, Paradis V, Conti M, Holstege A, Richet F, Devete J. In situ detection of lipid peroxidation by-products as markers of renal ischemia injuries in rat kidneys. J Urol 1999; 162: 553-7.10.1016/S0022-5347(05)68626-0Search in Google Scholar
43. Sigh D, Chopra K. The effect of naringin, a bioflavonoid on ischemiareperfusion- induced renal injury in rats. Pharmacol Res 2004; 50: 187-193.10.1016/j.phrs.2004.01.007Search in Google Scholar PubMed
44. Baud L, Ardaillou R. Involvement of reactive oxygen species in kidney damage. Br Med Bull 1993; 49: 621-9.10.1093/oxfordjournals.bmb.a072635Search in Google Scholar PubMed
45. Dreyer WJ, Smith CW, Michael LH, Rossen RD, Hughes BJ, Entman ML, et al. Canine neutrophil activation by cardiac lymph obtained during reperfusion of ischemic myocardium. Circ Res 1989; 65: 1751-62.10.1161/01.RES.65.6.1751Search in Google Scholar
46. Prescott SM, Zimmerman GA, Stafforini DM, McIntyre TM. Plateletactivating factor and related lipid mediators. Annu Rev Biochem 2000; 69: 419-45.10.1146/annurev.biochem.69.1.419Search in Google Scholar PubMed
47. Lloberas N, Torras J, Herrero-Fresneda I, Cruzado JM, Riera M, Hurtado I, et al. Postischemic renal oxidative stress induces inflammatory response through PAF and oxidized phospholipids. Prevention by antioxidant treatment. FASEB J 2002; 16: 908-10. 10.1096/fj.01-0880fjeSearch in Google Scholar PubMed
© 2015
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
