Background Acute renal failure from ischemia significantly contributes to morbidity and mortality in clinical settings, and strategies to improve renal resistance to ischemia are urgently needed. Here, we identified a novel pathway of renal protection from ischemia using ischemic preconditioning (IP). Methods and Findings For this purpose, we utilized a recently developed model of renal ischemia and IP via a hanging weight system that allows repeated and atraumatic occlusion of the renal artery in mice, followed by measurements of specific parameters or renal functions. Studies in gene-targeted mice for each individual adenosine receptor (AR) confirmed renal protection by IP in A1？/？, A2A？/？, or A3AR？/？ mice. In contrast, protection from ischemia was abolished in A2BAR？/？ mice. This protection was associated with corresponding changes in tissue inflammation and nitric oxide production. In accordance, the A2BAR-antagonist PSB1115 blocked renal protection by IP, while treatment with the selective A2BAR-agonist BAY 60–6583 dramatically improved renal function and histology following ischemia alone. Using an A2BAR-reporter model, we found exclusive expression of A2BARs within the reno-vasculature. Studies using A2BAR bone-marrow chimera conferred kidney protection selectively to renal A2BARs. Conclusions These results identify the A2BAR as a novel therapeutic target for providing potent protection from renal ischemia.
References
[1]
Abuelo JG (2007) Normotensive ischemic acute renal failure. N Engl J Med 357: 797–805.
[2]
Thadhani R, Pascual M, Bonventre JV (1996) Acute renal failure. N Engl J Med 334: 1448–1460.
[3]
Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW (2005) Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 16: 3365–3370.
[4]
Gelman S (1995) The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 82: 1026–1060.
[5]
Mehta RL (2005) Acute renal failure and cardiac surgery: marching in place or moving ahead. J Am Soc Nephrol 16: 12–14.
[6]
Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, et al. (2006) Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol 17: 1724–1734.
[7]
Zhou W, Farrar CA, Abe K, Pratt JR, Marsh JE, et al. (2000) Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest 105: 1363–1371.
[8]
Hart ML, Walsh MC, Stahl GL (2004) Initiation of complement activation following oxidative stress. In vitro and in vivo observations. Mol Immunol 41: 165–171.
[9]
Hansen PB, Schnermann J (2003) Vasoconstrictor and vasodilator effects of adenosine in the kidney. Am J Physiol Renal Physiol 285: F590–F599.
[10]
Vallon V, Muhlbauer B, Osswald H (2006) Adenosine and kidney function. Physiol Rev 86: 901–940.
[11]
Morrison RR, Talukder MA, Ledent C, Mustafa SJ (2002) Cardiac effects of adenosine in A(2A) receptor knockout hearts: uncovering A(2B) receptors. Am J Physiol Heart Circ Physiol 282: H437–444.
[12]
Gross ER, Gross GJ (2007) Pharmacologic therapeutics for cardiac reperfusion injury. Expert Opin Emerg Drugs 12: 367–388.
[13]
Sitkovsky M, Lukashev D (2005) Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol 5: 712–721.
[14]
Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, et al. (2004) Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 22: 657–682.
[15]
Linden J (2005) Adenosine in tissue protection and tissue regeneration. Mol Pharmacol 67: 1385–1387.
[16]
Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14: 1315–1323.
[17]
Xu Z, Mueller RA, Park SS, Boysen PG, Cohen MV, et al. (2005) Cardioprotection with adenosine A2 receptor activation at reperfusion. J Cardiovasc Pharmacol 46: 794–802.
[18]
Merighi S, Mirandola P, Varani K, Gessi S, Leung E, et al. (2003) A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol Ther 100: 31–48.
[19]
Grenz A, Zhang H, Hermes M, Eckle T, Klingel K, et al. (2007) Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury. FASEB J 21: 2863–2873.
[20]
Grenz A, Zhang H, Eckle T, Mittelbronn M, Wehrmann M, et al. (2007) Protective role of ecto-5′-nucleotidase (CD73) in renal ischemia. J Am Soc Nephrol 18: 833–845.
[21]
Eltzschig HK, Abdulla P, Hoffman E, Hamilton KE, Daniels D, et al. (2005) HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J Exp Med 202: 1493–1505.
[22]
Eltzschig HK, Thompson LF, Karhausen J, Cotta RJ, Ibla JC, et al. (2004) Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 104: 3986–3992.
[23]
Thompson LF, Eltzschig HK, Ibla JC, Van De Wiele CJ, Resta R, et al. (2004) Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med 200: 1395–1405.
[24]
Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA, et al. (2003) Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J Exp Med 198: 783–796.
[25]
Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF, et al. (2007) A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 111: 2024–2035.
Kohler D, Eckle T, Faigle M, Grenz A, Mittelbronn M, et al. (2007) CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury. Circulation 116: 1784–1794.
[28]
Eckle T, Krahn T, Grenz A, Kohler D, Mittelbronn M, et al. (2007) Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors. Circulation 115: 1581–1590.
[29]
Day YJ, Huang L, McDuffie MJ, Rosin DL, Ye H, et al. (2003) Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J Clin Invest 112: 883–891.
[30]
Lee HT, Gallos G, Nasr SH, Emala CW (2004) A1 adenosine receptor activation inhibits inflammation, necrosis, and apoptosis after renal ischemia-reperfusion injury in mice. J Am Soc Nephrol 15: 102–111.
[31]
Delacretaz E (2006) Clinical practice. Supraventricular tachycardia. N Engl J Med 354: 1039–1051.
[32]
Bertolet BD, Anand IS, Bryg RJ, Mohanty PK, Chatterjee K, et al. (1996) Effects of A1 adenosine receptor agonism using N6-cyclohexyl-2′-O-methyladenosine in patients with left ventricular dysfunction. Circulation 94: 1212–1215.
[33]
Huang DY, Vallon V, Zimmermann H, Koszalka P, Schrader J, et al. (2006) Ecto-5′-nucleotidase (cd73)-dependent and -independent generation of adenosine participates in the mediation of tubuloglomerular feedback in vivo. Am J Physiol Renal Physiol 291: F282–288.
[34]
Castrop H, Huang Y, Hashimoto S, Mizel D, Hansen P, et al. (2004) Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73-deficient mice. J Clin Invest 114: 634–642.
[35]
Krieg T, Cohen MV, Downey JM (2003) Mitochondria and their role in preconditioning's trigger phase. Basic Res Cardiol 98: 228–234.
[36]
Downey JM, Davis AM, Cohen MV (2007) Signaling pathways in ischemic preconditioning. Heart Fail Rev 12: 181–188.
[37]
Chatterjee PK, Patel NS, Sivarajah A, Kvale EO, Dugo L, et al. (2003) GW274150, a potent and highly selective inhibitor of iNOS, reduces experimental renal ischemia/reperfusion injury. Kidney Int 63: 853–865.
[38]
Basile DP (2007) The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int 72: 151–156.
[39]
Eckle T, Grenz A, Kohler D, Redel A, Falk M, et al. (2006) Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice. Am J Physiol Heart Circ Physiol 291: H2533–2540.
[40]
Grenz A, Eckle T, Zhang H, Huang DY, Wehrmann M, et al. (2007) Use of a hanging-weight system for isolated renal artery occlusion during ischemic preconditioning in mice. Am J Physiol Renal Physiol 292: F475–F485.
[41]
Salvatore CA, Tilley SL, Latour AM, Fletcher DS, Koller BH, et al. (2000) Disruption of the A(3) adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J Biol Chem 275: 4429–4434.
[42]
Sun D, Samuelson LC, Yang T, Huang Y, Paliege A, et al. (2001) Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc Natl Acad Sci U S A 98: 9983–9988.
[43]
Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, et al. (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388: 674–678.
[44]
Yang D, Zhang Y, Nguyen HG, Koupenova M, Chauhan AK, et al. (2006) The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest 116: 1913–1923.
[45]
Huang DY, Boini KM, Osswald H, Friedrich B, Artunc F, et al. (2006) Resistance of mice lacking the serum- and glucocorticoid-inducible kinase SGK1 against salt-sensitive hypertension induced by a high-fat diet. Am J Physiol Renal Physiol 291: F1264–F1273.
[46]
Kloor D, Delabar U, Muhlbauer B, Luippold G, Osswald H (2002) Tissue levels of S-adenosylhomocysteine in the rat kidney: effects of ischemia and homocysteine. Biochem Pharmacol 63: 809–815.
[47]
Jablonski P, Howden BO, Rae DA, Birrell CS, Marshall VC, et al. (1983) An experimental model for assessment of renal recovery from warm ischemia. Transplantation 35: 198–204.
[48]
Horny HP, Sillaber C, Menke D, Kaiserling E, Wehrmann M, et al. (1998) Diagnostic value of immunostaining for tryptase in patients with mastocytosis. Am J Surg Pathol 22: 1132–1140.
[49]
Yang Z, Day YJ, Toufektsian MC, Ramos SI, Marshall M, et al. (2005) Infarct-sparing effect of A2A-adenosine receptor activation is due primarily to its action on lymphocytes. Circulation 111: 2190–2197.
[50]
Lee HT, Emala CW (2000) Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A(1) and A(3) receptors. Am J Physiol Renal Physiol 278: F380–F387.
[51]
Lee HT, Emala CW (2002) Preconditioning and adenosine protect human proximal tubule cells in an in vitro model of ischemic injury. J Am Soc Nephrol 13: 2753–2761.
[52]
Eckle T, Fullbier L, Wehrmann M, Khoury J, Mittelbronn M, et al. (2007) Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury. J Immunol 178: 8127–8137.
Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7: 758–765.
[55]
Haugen E, Nath KA (1999) The involvement of oxidative stress in the progression of renal injury. Blood Purif 17: 58–65.
[56]
Yan L, Muller CE (2004) Preparation, properties, reactions, and adenosine receptor affinities of sulfophenylxanthine nitrophenyl esters: toward the development of sulfonic acid prodrugs with peroral bioavailability. J Med Chem 47: 1031–1043.
[57]
Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, et al. (2007) Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med 204: 2089–2102.
[58]
Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, et al. (2003) Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation 108: 79–85.
[59]
Yang CW, Li C, Jung JY, Shin SJ, Choi BS, et al. (2003) Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. FASEB J 17: 1754–1755.
[60]
Ozuyaman B, Ding Z, Buchheiser A, Koszalka P, Braun N, et al. (2006) Adenosine produced via the CD73/ecto-5′-nucleotidase pathway has no impact on erythropoietin production but is associated with reduced kidney weight. Pflugers Arch 452: 324–331.
[61]
Grenz A, Zhang H, Weingart J, von Wietersheim S, Eckle T, et al. (2007) Lack of effect of extracellular adenosine generation and signalling on renal erythropoietin secretion during hypoxia. Am J Physiol Renal Physiol. 00243.02007.
[62]
Liu Y, Yang XM, Iliodromitis EK, Kremastinos DT, Dost T, et al. (2008) Redox signaling at reperfusion is required for protection from ischemic preconditioning but not from a direct PKC activator. Basic Res Cardiol 103: 54–59.
[63]
Philipp S, Yang XM, Cui L, Davis AM, Downey JM, et al. (2006) Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovasc Res 70: 308–314.
[64]
Kuno A, Critz SD, Cui L, Solodushko V, Yang XM, et al. (2007) Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A2b-dependent signaling during early reperfusion. J Mol Cell Cardiol 43: 262–271.
[65]
Okusa MD, Linden J, Huang L, Rosin DL, Smith DF, et al. (2001) Enhanced protection from renal ischemia-reperfusion [correction of ischemia:reperfusion] injury with A(2A)-adenosine receptor activation and PDE 4 inhibition. Kidney Int 59: 2114–2125.
[66]
Day YJ, Huang L, Ye H, Li L, Linden J, et al. (2006) Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and IFN-gamma. J Immunol 176: 3108–3114.
