title: Adenosine and protection from acute kidney injury.
abstract: OBJECTIVE
  Acute kidney injury (AKI) is a major clinical problem without effective therapy. Development of AKI among hospitalized patients drastically increases mortality and morbidity. With increases in complex surgical procedures together with a growing elderly population, the incidence of AKI is rising. Renal adenosine receptor manipulation may have great therapeutic potential in mitigating AKI. In this review, we discuss renal adenosine receptor biology and potential clinical therapies for AKI.
  
  
  RESULTS
  The four adenosine receptor subtypes (A(1)AR, A(2A)AR, A(2B)AR, and A(3)AR) have diverse effects on the kidney. The pathophysiology of AKI may dictate the specific adenosine receptor subtype activation needed to produce renal protection. The A(1)AR activation in renal tubules and endothelial cells produces beneficial effects against ischemia and reperfusion injury by modulating metabolic demand, decreasing necrosis, apoptosis, and inflammation. The A(2A)AR protects against AKI by modulating leukocyte-mediated renal and systemic inflammation, whereas the A(2B)AR activation protects by direct activation of renal parenchymal adenosine receptors. In contrast, the A(1)AR antagonism may play a protective role in nephrotoxic AKI and radiocontrast induced nephropathy by reversing vascular constriction and inducing naturesis and diuresis. Furthermore, as the A(3)AR activation exacerbates apoptosis and tissue damage due to renal ischemia and reperfusion, selective A(3)AR antagonism may hold promise to attenuate renal ischemia and reperfusion injury. Finally, renal A(1)AR activation also protects against renal endothelial dysfunction caused by hepatic ischemia and reperfusion injury.
  
  
  CONCLUSIONS
  Despite the current lack of therapies for the treatment and prevention of AKI, recent research suggests that modulation of renal adenosine receptors holds promise in treating AKI and extrarenal injury.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032-3784, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Yap
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D019610:Cytoprotection; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058906:Purinergic P1 Receptor Agonists / Q000627:therapeutic use*; D058915:Purinergic P1 Receptor Antagonists / Q000627:therapeutic use*; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D000241:Adenosine
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Oct;293(4):R1538-44
references.pmid: 17652366
references.citation: Am J Physiol Regul Integr Comp Physiol. 2006 Oct;291(4):R959-69
references.pmid: 16728466
references.citation: Am J Physiol Renal Physiol. 2002 Jan;282(1):F10-8
references.pmid: 11739107
references.citation: Oncogene. 2010 Sep 30;29(39):5346-58
references.pmid: 20661219
references.citation: J Pharmacol Exp Ther. 2010 Jun;333(3):736-47
references.pmid: 20308331
references.citation: J Immunol. 2004 Jul 15;173(2):1380-9
references.pmid: 15240734
references.citation: Am J Physiol Renal Physiol. 2000 Nov;279(5):F809-18
references.pmid: 11053040
references.citation: Physiol Rev. 2006 Jul;86(3):901-40
references.pmid: 16816141
references.citation: Curr Opin Nephrol Hypertens. 2000 Jul;9(4):427-34
references.pmid: 10926180
references.citation: Biochem Pharmacol. 2001 Feb 15;61(4):443-8
references.pmid: 11226378
references.citation: Am J Kidney Dis. 2004 Jul;44(1):12-24
references.pmid: 15211433
references.citation: Handb Exp Pharmacol. 2009;(193):443-70
references.pmid: 19639291
references.citation: Am J Physiol Renal Physiol. 2003 Feb;284(2):F267-73
references.pmid: 12388399
references.citation: Scand J Clin Lab Invest Suppl. 2008;241:6-11
references.pmid: 18569958
references.citation: Eur J Pharmacol. 1996 Mar 18;298(3):293-7
references.pmid: 8846829
references.citation: Am J Physiol Renal Physiol. 2005 Apr;288(4):F722-31
references.pmid: 15561971
references.citation: J Am Soc Nephrol. 2007 Mar;18(3):833-45
references.pmid: 17267736
references.citation: Microvasc Res. 2002 Jan;63(1):61-9
references.pmid: 11749073
references.citation: Contrib Nephrol. 2010;165:1-8
references.pmid: 20427949
references.citation: Contrib Nephrol. 2010;165:153-158
references.pmid: 20427965
references.citation: Crit Care. 2005;9(6):R700-9
references.pmid: 16280066
references.citation: J Am Soc Nephrol. 2004 Jan;15(1):102-11
references.pmid: 14694162
references.citation: Am J Physiol Renal Physiol. 2005 Aug;289(2):F369-76
references.pmid: 15784841
references.citation: Circulation. 2002 Mar 19;105(11):1348-53
references.pmid: 11901047
references.citation: Adv Chronic Kidney Dis. 2008 Jul;15(3):284-96
references.pmid: 18565479
references.citation: Handb Exp Pharmacol. 2009;(193):25-58
references.pmid: 19639278
references.citation: Am J Physiol Renal Physiol. 2002 May;282(5):F844-52
references.pmid: 11934694
references.citation: Best Pract Res Clin Anaesthesiol. 2008 Mar;22(1):193-208
references.pmid: 18494397
references.citation: Mini Rev Med Chem. 2007 Jun;7(6):559-69
references.pmid: 17584155
references.citation: Cell Death Differ. 2007 Jul;14(7):1315-23
references.pmid: 17396131
references.citation: Blood. 2008 Feb 15;111(4):2024-35
references.pmid: 18056839
references.citation: Am J Physiol Renal Physiol. 2000 Mar;278(3):F380-7
references.pmid: 10710542
references.citation: Annu Rev Pharmacol Toxicol. 2001;41:775-87
references.pmid: 11264476
references.citation: Exp Cell Res. 1998 Sep 15;243(2):383-97
references.pmid: 9743598
references.citation: FASEB J. 2008 Feb;22(2):445-54
references.pmid: 17898087
references.citation: Kidney Int. 2007 Jun;71(12):1249-61
references.pmid: 17429344
references.citation: J Exp Med. 2004 Dec 6;200(11):1395-405
references.pmid: 15583013
references.citation: Lab Invest. 2010 Mar;90(3):476-95
references.pmid: 20065944
references.citation: Sci Signal. 2009 Feb 03;2(56):pe6
references.pmid: 19193605
references.citation: J Am Soc Nephrol. 2005 Nov;16(11):3365-70
references.pmid: 16177006
references.citation: FASEB J. 2007 Sep;21(11):2863-73
references.pmid: 17442731
references.citation: Science. 2006 Dec 15;314(5806):1792-5
references.pmid: 17170310
references.citation: PLoS Med. 2008 Jun 24;5(6):e137
references.pmid: 18578565
references.citation: Science. 2010 Oct 15;330(6002):362-6
references.pmid: 20947763
references.citation: Am J Kidney Dis. 2001 Sep;38(3):610-8
references.pmid: 11532695
references.citation: J Am Soc Nephrol. 2011 Jan;22(1):14-20
references.pmid: 21209250
references.citation: Blood Purif. 2010;29(3):300-7
references.pmid: 20130395
references.citation: Blood. 2009 Jan 1;113(1):224-32
references.pmid: 18812468
references.citation: Kidney Int. 2009 Apr;75(8):809-23
references.pmid: 19190680
references.citation: Am J Physiol Renal Physiol. 2004 Feb;286(2):F298-306
references.pmid: 14600029
references.citation: J Clin Invest. 2006 Jul;116(7):1835-7
references.pmid: 16823484
references.citation: Am J Physiol Renal Physiol. 2006 Jun;290(6):F1367-75
references.pmid: 16418301
references.citation: Curr Heart Fail Rep. 2008 Jun;5(2):105-9
references.pmid: 18765081
references.citation: Microvasc Res. 2009 Jan;77(1):8-12
references.pmid: 18929580
references.citation: J Am Coll Cardiol. 2011 May 10;57(19):1899-907
references.pmid: 21545947
references.citation: Inflamm Res. 1997 May;46(5):180-4
references.pmid: 9197988
references.citation: Handb Exp Pharmacol. 2011;(200):391-412
references.pmid: 20859805
references.citation: Eur J Pharmacol. 2003 Apr 18;466(3):323-9
references.pmid: 12694816
references.citation: Contrib Nephrol. 2007;156:32-8
references.pmid: 17464113
references.citation: Trends Pharmacol Sci. 1998 May;19(5):184-91
references.pmid: 9652191
references.citation: J Clin Invest. 2003 Sep;112(6):883-91
references.pmid: 12975473
references.citation: Can J Physiol Pharmacol. 2000 May;78(5):428-32
references.pmid: 10841439
references.citation: Lab Invest. 2011 Jan;91(1):63-84
references.pmid: 20697374
references.citation: Biochem Biophys Res Commun. 1996 Feb 27;219(3):904-10
references.pmid: 8645277
references.citation: Lab Invest. 2009 Feb;89(2):196-208
references.pmid: 19079326
references.citation: Am J Physiol Renal Physiol. 2007 Dec;293(6):F1847-57
references.pmid: 17928414